Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[C:19]3[CH3:23])[C:5]2[C:6](=[O:10])[NH:7][N:8]=[CH:9][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[NH2:33][C@@H:34]1[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]1[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].O>CN1C(=O)CCC1>[C:43]([O:42][C:41](=[O:47])[NH:40][C@H:35]1[CH2:36][CH2:37][CH2:38][CH2:39][C@H:34]1[NH:33][C:2]1[N:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[C:19]3[CH3:23])[C:5]2[C:6](=[O:10])[NH:7][N:8]=[CH:9][C:4]=2[CH:3]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: Cc1c[nH]c2c(Nc3nc(Cl)cc4cn[nH]c(=O)c34)cccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2c(Nc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)cc4cn[nH]c(=O)c34)cccc12
Temperature: 120 °C

Procedure:
To 7-chloro-5-(3-methyl-1H-indol-7-ylamino)-3H-pyrido[3,4-d]pyridazin-4-one (177 mg, 0.543 mmol) in NMP (1 ml) in a sealable glass vial, was added DIPEA (0.190 ml, 1.087 mmol) and tert-butyl(1S,2R)-2-aminocyclohexylcarbamate (233 mg, 1.087 mmol). The vial was capped to close and the reaction mixture was heated on a sandbath at 120° C. for 3 days. The resulting mixture was poured into water (20 ml), and extracted with EtOAc (20 ml). The organic phase was washed with water and brine, dried over Na2SO4, then concentrated under vacuum. The residue was triterated with DCM, then collected by filtration and dried to give a gummy solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)=[CH:14][C:13]=1[CH2:23][NH2:24]>ClCCl>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[CH:21][NH:20][N:19]=2)=[CH:14][C:13]=1[CH2:23][NH:24][CH:5]=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: NCc1cc(-c2cc[nH]n2)ccc1Cl
Solvent: O=CO
Solvent: ClCCl
Product: O=CNCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of acetic anhydride (0.82 mL, 9.7 mmol) and formic acid (0.4 mL, 9.7 mmol) was heated to 50° C. for 30 minutes and then cooled to 0° C. 2-Chloro-5-(1H-pyrazol-3-yl)benzenemethanamine (i.e. the product of Step C) (1.0 g, 4.8 mmol) was added, and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was then diluted with dichloromethane, washed with saturated sodium bicarbonate solution and brine, then dried (Na2SO4) and concentrated. The crude residue was purified by preparative thin layer chromatography (TLC) (2% methanol in chloroform as eluant) to provide the title product as a solid (0.5 g).
Reaction SMILES: [CH3:1][NH2:2].C(O)(=O)C.Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([Cl:17])[N:11]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[N:9]=1.O>O1CCCC1>[Cl:17][C:12]1[C:13]([N+:14]([O-:16])=[O:15])=[C:8]([NH:2][CH3:1])[N:9]=[C:10]([NH:18][C:19](=[O:21])[CH3:20])[N:11]=1
Reactant: CC(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(NC(C)=O)nc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
A mixed solution (reagent A) of 2 liters of a 40% aqueous solution of methylamine and 1.5 liters of acetic acid previously prepared at not higher than 10° C. was weighed and taken out in an amount of 1.8 liters and added dropwise into a solution of 1.5 kg of N1-(4,6-dichloro-5-nitro-2-pyrimidinyl)acetamide in 15 liters of tetrahydrofuran with stirring under ice-cooling over 1 hour. The addition was carried out keeping the bulk temperature at 4° C. or lower. After the mixture was stirred for 30 minutes under ice-cooling, 450 ml of the reagent A was further added. After further 30 minutes, 450 ml of the reagent A was added again followed by stirring for 40 minutes. Ice (4.5 kg) was added to the reaction mixture followed by adding 10 liters of cold water. The resulting crystals were collected by filtration and washed with 1 liter of water twice and with 1 liter of ether twice. Then it was dried at 50° C. for 6 hours to give 1253 g of N1-(4-Chloro-6-methylamino-5-nitro-2-pyrimidinyl)acetamide. The yield was 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:14][CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])=[N:14][CH:13]=1
Reactant: COC(=O)c1ccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)nc1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1ccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)nc1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 6-{[phenyl-(3-phenyl-propynoyl)-amino]-methyl}-nicotinic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.93 (s, 3H), 5.10 (s, 2H), 6.54 (d, 1H), 6.57-6.75 (m, 2H), 7.08 (t, 1H), 7.28-7.44 (m, 10H), 8.20 (d, 1H), 9.16 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:18]([OH:29])[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:15]=[CH:16][CH:17]=1>>[OH:29][CH:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:8]([CH:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][CH2:6]2)=[O:10])[CH:13]=1)[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCC(O)c1cccc(N)c1
Reactant: O=C1CCC(C(=O)O)CN1
Product: CC(C)(C)OC(=O)NCCC(O)c1cccc(NC(=O)C2CCC(=O)NC2)c1

Procedure:
Condensation between 6-oxopiperidine-3-carboxylic acid and tert-butyl (3-(3-aminophenyl)-3-hydroxypropyl)carbamate gives tert-butyl (3-hydroxy-3-(3-(6-oxopiperidine-3-carboxamido)phenyl)propyl)carbamate.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH:29]1([CH2:32][NH:33][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:13])[CH2:31][CH2:30]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCC1CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC3CC3)ccc21
Yield: 23.6 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid cyclopropylmethyl-amide (24 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (90 mg), cyclopropane-methylamine (16 mg), DPPA (48 uL), and DIEA (39 uL). LC/MS: m/z 462.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.16 (bs, 1H), 8.30 (s, 1H), 7.87 (s, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.50 (d, 1H), 7.26 (d, 1H), 7.12 (d, 1H), 3.40 (bs, 3H), 2.94 (t, 2H), 0.89-0.78 (m, 1H), 0.21 (d, 2H), 0.02 (d, 2H).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:32])[C@@H:8]([NH:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][NH:24]C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([O:6][C:7](=[O:32])[C@@H:8]([NH:15][CH2:16][CH:17]2[CH2:18][CH2:19][CH:20]([CH2:23][NH2:24])[CH2:21][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(CN[C@H](C(=O)OC2CCCC2)c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCC(CN[C@H](C(=O)OC2CCCC2)c2ccccc2)CC1
Reaction time: 2 h
Yield: 75.5 %

Procedure:
(S)-{[4-(tert-Butoxycarbonylamino-methyl)-cyclohexylmethyl]-amino}-phenyl-acetic acid cyclopentyl ester (223 mg, 0.5 mmol) was stirred in DCM (4 ml), TFA (1 ml) was added and the mixture was stirred at r.t, for 2 h. The solution was concentrated in vacuo, taken up in DCM, washed twice with a saturated solution of NaHCO3 and once with a saturated solution of brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to yield the expected amine as a yellow oil (130 mg, 75% yield). LCMS purity 100%, m/z 345 [M++H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[C@@H:9](O)[C@H:8]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:7]=2[CH:24]=1)#[N:2].[OH-].[Na+].O1CCOCC1>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:7]=2[CH:24]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)[C@@H](n1ccccc1=O)[C@H](O)C(CF)(CF)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)C(n1ccccc1=O)=CC(CF)(CF)O2

Procedure:
A mixture of 0.13 g of trans-6-cyano-2,2-bisfluoromethyl-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran-3-ol, 0.13 g of sodium hydroxide on support and 2 ml of dioxane was refluxed for 45 minutes. Water was added thereto and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was recrystallized from ethyl acetate to obtain 6-cyano-2,2-bisfluoromethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran represented by the following formula having a melting point of 174°-175° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.Br.Br.Br.[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][NH:37][CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]>>[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][N:37]([CH2:5][C:4]6[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=6)[CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]
Reactant: O=Cc1cccc(O)c1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3cccc(O)c3)C4)n[nH]c2c1
Yield: 62 %

Procedure:
The title compound was prepared from 3-hydroxy-benzaldehyde (24.2 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 18. The crude material was purified by HPLC Method A to afford 39.6 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](CBr)=[N:7]1)[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([N:18]=[N+:19]=[N-:20])=[N:7]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)Cn1nc(CBr)c2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(N=[N+]=[N-])c2cccnc21
Temperature: 80 °C
Yield: 109.8 %

Procedure:
A mixture of (3-(bromomethyl)-pyrazolo[3,4-b]pyridine-1-yl)acetic acid ethyl ester (0.5 mmol, 1 eq.) and sodium azide (1 mmol, 2 eq.) in 1 mL of DMF was heated at 80° C. for 1 h. The resultant mixture was cooled to rt, diluted with 150 mL of EtOAc, washed with water (40 mL×3), brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solvent was removed in vacuo to provide 135.2 mg desired product: HPLC retention time=1.84 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=261.1. found=261.4.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C)Oc1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)Oc1ccccc1CBr

Procedure:
A mixture of 6 g (0.029 mol) of ester obtained from step A, 5.6 g (0.031 mol) of N-bromosuccinimide and 100 mg of benzoyl peroxide in 100 ml of CCl4 is heated to reflux while irradiated with a sun-lamp, for 1 hour. The reaction mixture is cooled down and filtered to dryness to give ethyl 2-(2-bromomethylphenoxy)propionate which is used directly in the next step.
Reaction SMILES: O.[CH3:2][C:3]([C:6]1[CH:7]=[C:8]([S:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[S:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)([CH3:5])[CH3:4].O.[OH-].[Li+].Cl>CO>[CH3:15][C:12]([C:10]1[CH:9]=[C:8]([S:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]2[S:23][CH2:24][C:25]([OH:27])=[O:26])[CH:7]=[C:6]([C:3]([CH3:2])([CH3:4])[CH3:5])[CH:11]=1)([CH3:13])[CH3:14]
Reactant: COC(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Water was added to a solution of the compound of Example 4 (9.2 g, 0.0255 moles) in methyl alcohol (100 ml) until the solution became cloudy. Lithium hydroxide hydrate (1.75 g, 0.0675 moles) was added, and the reaction mixture was stirred at room temperature. Periodically, water was added to make the solution cloudy. After 6 hours, the solution was made acidic with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate, filtered, and concentrated to give the crude product as an oil. The product was purified by silica gel chromatography. The structure assignment was supported by NMR and elemental analysis.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:16](=[O:24])[CH:15]([CH2:25][C:26]([OH:28])=O)[S:14]1.[NH:30]1[CH2:35][CH2:34][CH:33]([N:36]2[C:44]3[C:39](=[N:40][CH:41]=[CH:42][CH:43]=3)[NH:38][C:37]2=[O:45])[CH2:32][CH2:31]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]1[N:17]([CH2:18][CH2:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:16](=[O:24])[C@H:15]([CH2:25][C:26]([N:30]2[CH2:31][CH2:32][CH:33]([N:36]3[C:44]4[C:39](=[N:40][CH:41]=[CH:42][CH:43]=4)[NH:38][C:37]3=[O:45])[CH2:34][CH2:35]2)=[O:28])[S:14]1
Reactant: CN(C)CCNc1c(F)cccc1C1SC(CC(=O)O)C(=O)N1CCC(C)(C)C
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CN(C)CCNc1c(F)cccc1C1S[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)C(=O)N1CCC(C)(C)C

Procedure:
2-(2-(2-(2-(Dimethylamino)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (125.5 mg, 0.295 mmol), 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (171.8 mg, 0.5900 mmol), EDC (113.1 mg, 0.5900 mmol), HOBt (90.35 mg, 0.5900 mmol), and DIEA (152.5 mg, 205.5 μL, 1.180 mmol) were stirred in DMF (6 mL) at RT overnight. The mixture was diluted with EtOAc and washed with water and a saturated sodium bicarbonate solution. The aqueous layer was back extracted, all organic layers were combined, washed with brine, dried over (MgSO4), concentrated to an oil. The crude oil was purified by reverse phase column chromatography with ACN/water to give desired 1-(1-(2-((5S)-2-(2-(2-(dimethylamino)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc(N)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
A solution of tert-butyl (4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)carbamate (1.6 g, 4.81 mmol) in MeOH (25 mL) and THF (25 mL) was treated with NH4Cl (7.73 g, 144 mmol) followed by the portion-wise addition of zinc dust (3.15 g, 48.1 mmol) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth, washed with THF and EtOAc and the filtrate concentrated to dryness. The residue was suspended in THF, sonicated, the solids removed via filtration and the filtrate concentrated to dryness. The material was suspended in DCM, washed with water, the aqueous layer back-extracted with DCM and the combined organics were dried over Na2SO4 and concentrated to dryness to afford tert-butyl (4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)carbamate (1.6 g, 110%). 1H NMR (400 MHz, DMSO-d6): δ 9.76 (s, 1H), 8.06 (d, J=5.7 Hz, 1H), 7.78 (d, J=2.9 Hz, 1H), 7.26-7.25 (m, 2H), 6.55-6.48 (m, 2H), 6.01 (s, 2H), 1.40 (s, 9H); MS (ESI) m/z: 303.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])([CH3:15])[CH3:14])/[C:8]([OH:10])=O)[N:6]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O.[NH2:64][C@H:65]1[CH2:68][N:67]([C:69]([NH:71][S:72]([N:75]2[CH2:79][CH2:78][N:77]([NH:80][C:81](=[O:90])[C:82]3[CH:87]=[CH:86][C:85]([OH:88])=[C:84]([OH:89])[CH:83]=3)[C:76]2=[O:91])(=[O:74])=[O:73])=[O:70])[C:66]1=[O:92]>CN(C)C=O.C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][C:13]([CH3:14])([CH3:15])[C:16]([O:18][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:17])[C:8]([NH:64][CH:65]2[CH2:68][N:67]([C:69]([NH:71][S:72]([N:75]3[CH2:79][CH2:78][N:77]([NH:80][C:81](=[O:90])[C:82]4[CH:87]=[CH:86][C:85]([OH:88])=[C:84]([OH:89])[CH:83]=4)[C:76]3=[O:91])(=[O:73])=[O:74])=[O:70])[C:66]2=[O:92])=[O:10])[N:6]=1
Reactant: N[C@H]1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C2=O)C1=O
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3ccc(O)c(O)c3)C2=O)C1=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.9 %

Procedure:
(Z)-2-Amino-α-[[1-(diphenylmethoxycarbonyl)-1-methylethoxy]imino]-4-thiazoleacetic acid (0.88 g, 0.002 mol) was dissolved in 20 ml of dimethylformamide followed by 0.3 g of N-hydroxybenzotriazole (containing 13% water), followed by 0.5 g of dicyclohexylcarbodiimide and 0.28 ml of triethylamine. The mixture was stirred at room temperature for 1 hour, then 1.08 g (0.002 mol) of (S)-3-amino-N-[[3-[(3,4-dihydroxybenzoyl)amino]-2-oxo-1-imidazolidinyl]sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate salt (see Example 1D) was added. The mixture was stirred at room temperature overnight. The precipitate (dicyclohexylurea) was filtered off and the filtrate evaporated in vacuo. Trituration of the remaining syrup with ether yielded 1.8 g of the title compound in crude form.
Reaction SMILES: [C:1]([NH:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][SH:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:17]([F:21])([F:20])[CH2:18][Cl:19]>[OH-].[Na+].CN(C=O)C>[C:1]([NH:8][CH:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][S:12][C:17]([F:21])([F:20])[CH2:18][Cl:19])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: FC(F)(Cl)CCl
Reactant: CC(C)(C)OC(=O)NC(CCS)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCSC(F)(F)CCl)C(=O)O
Temperature: 50 °C

Procedure:
Ex-18a) A solution of N-Boc-D,L-homocysteine (5 mmol) in NaOH (5 mL, 2N) was slowly added to a stirred solution of 1,2-dichloro-1,1-difluoroethane (5 mmol) in DMF. The resulting solution was then warmed to 50° C. for 16 hours. The reaction solution was then poured onto EtOAc and extracted with citric acid (5%) and brine, dried (Na2SO4) and concentrated in vacuo. The material was purified by flash column chromatography to yield N-Boc-S-(2-chloro-1,1-difluoroethyl)-D,L-homocysteine. Example 18 is prepared in the same manner as described for Example 17 starting with N-Boc-S-(2-chloro-1,1-difluoroethyl)-D,L-homocysteine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-])=O)[CH:3]=1>[Zn]>[NH2:16][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Zn]
Product: CC(C)(C)OC(=O)Nc1ccc(Br)cc1N

Procedure:
The title compound was prepared from the tert-butyl 4-bromo-2-nitrophenylcarbamate (Example A1; 3 mmol) by reduction with zinc according to the general procedure B. Obtained as a yellow solid (58%), MS (EI) 287 [(M+1)+].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[CH2:8][CH2:7][C:6]([CH3:13])([CH3:12])[C:5]=2[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:3]1.C(O[CH:24](OC(C)(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>CN(C)C=O>[CH3:24][N:25]([CH:27]=[C:8]1[C:9](=[O:11])[C:10]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]=2[C:6]([CH3:13])([CH3:12])[CH2:7]1)[CH3:26]
Reactant: CCOC(=O)c1nn(C)c2c1C(C)(C)CCC2=O
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1C(C)(C)CC(=CN(C)C)C2=O
Yield: 87.1 %

Procedure:
A solution of ethyl 1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (4.8 g, 19.18 mmol) in anhydrous dimethylformamide (30 mL) was treated with dimethylformamide di-tert-butylacetal (9.19 mL, 38.35 mmol) at 65° C. for 2 hours. The mixture was evaporated to dryness and the crude material was crystallized from hexane to give the title compound (5.1 g, 87% yield).
Reaction SMILES: [NH3:1].[F:2][C:3]([F:19])([F:18])[C:4]1[CH:5]=[C:6]([S:14](Cl)(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1>>[F:2][C:3]([F:19])([F:18])[C:4]1[CH:5]=[C:6]([S:14]([NH2:1])(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N
Product: NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
An aqueous solution of NH3 (32%) is added at RT to a solution of 3,5-bis(trifluoromethyl)-benzene-sulfonylchloride in EtAc. The mixture obtained is stirred and two phases are obtained and are separated. The organic layer obtained is washed with 1 N HCl and H2O, and dried. Solvent of the organic solution obtained is evaporated. 3,5-Bis-trifluoromethyl-benzene sulfonamide is obtained.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]([CH3:53])=[C:49]([CH:52]=1)[C:50]#[N:51]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:46]=[CH:47][C:48]([CH3:53])=[C:49]([CH:52]=3)[C:50]#[N:51])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1ccc(N)cc1C#N
Product: Cc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cc1C#N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 5-amino-2-methyl-benzonitrile according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=394.1 [M+H]+.