Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[CH:6]=[CH:7][C:8]([OH:30])=[C:9]([C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[CH:21]=[CH:20][N:19]3[N:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:18]3[CH:17]=2)[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH2:28]([O:27][C:25]([C:24]1[CH:23]=[N:22][N:19]2[CH:20]=[CH:21][C:16]([N:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[C:9]3[CH:10]=[C:5]([F:4])[CH:6]=[CH:7][C:8]=3[O:30][CH2:2][CH3:3])=[CH:17][C:18]=12)=[O:26])[CH3:29]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)cc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCC)cc12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Iodoethane (0.17 g, 1.08 mmol) was added to a mixture of (R)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (Int-76) (0.2 g, 0.54 mmol) and K2CO3 (0.23 g, 1.62 mmol) in CH3CN (10 mL) and continued stirring at 80° C. for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by column chromatography (using silica gel and 2% ethyl acetate in hexane as eluent) to afford the desired compound (Int-77). MS (ESI): m/z 398.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]1[N:13]([CH3:26])[C:14](=[O:25])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:16][C:7]2=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:34]([F:39])([F:38])C([O-])=O.[Na+]>CN(C=O)C.O>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:34]([F:39])[F:38])[C:8]1[N:13]([CH3:26])[C:14](=[O:25])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:16][C:7]2=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: CC(=O)c1ccc2[nH]c3c(cc(-c4ccc(Cl)cc4Cl)c(=O)n3C)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F
Temperature: 100 °C

Procedure:
460 mg (1.19 mmol) of compound from preparation 1.9A, 6-acetyl-3-(2,4-dichlorophenyl)-1-methyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one, are dissolved in 7 ml of DMF and 2 ml of water. 543 mg (1.67 mmol) of caesium carbonate and 419 mg (2.75 mmol) of sodium chlorodifluoroacetate are added. The mixture is heated at 100° C. for 48 hours. It is allowed to return to ambient temperature. The reaction medium is poured into water, and the precipitate formed is filtered off and washed with water. The product is taken up in an EtOAc/MeOH mixture and adsorbed onto silica. Purification is carried out on a silica column, elution being carried out with a 50/50 EtOAc/cyclohexane mixture and then with EtOAc.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[F:9][C:10]([F:27])([F:26])[O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1.CCOCC>C[N+]([O-])=O>[N+:7]([C:13]1[CH:14]=[C:15]([CH:24]=[CH:25][C:12]=1[O:11][C:10]([F:9])([F:26])[F:27])[CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitronium tetrafluoroborate (3.97 g, 29.9 mmol) was added in portions over 5 min to N-(4-trifluoromethoxy-benzyl)-2,2-dimethyl-propionamide (4.1 g, 15 mmol) in MeNO2 (35 mL) and the mixture was stirred at rt for 1 h. The mixture was treated with ice and Et2O was added. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was treated with PE and the sub-title compound was filtered off.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C@H:18]([C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)[S:24][C:20]=1[C@@H:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=1)[CH3:19]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@H](C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@H](C)Oc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (S)-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (S)-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as orange oil. According to chiral HPLC (Chiralpak-ADH), the enantiomeric excess amounts to 69%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].C([O-])(=O)C.[K+].[CH3:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1>CN(C)C(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:21]1[S:20][C:19]([CH3:18])=[N:23][C:22]=1[CH3:24]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Reactant: Cc1csc(C)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc([N+](=O)[O-])ccc1-c1sc(C)nc1C
Yield: 62.1 %

Procedure:
In a microwave vial a mixture of 2-bromo-5-nitroanisole (600 mg, 2.53 mmol), potassium acetate (377 mg, 3.80 mmol) and tetrakis(triphenylphosphine)-palladium(0) (148 mg, 0.13 mmol) in N,N-dimethylacetamide (8 mL) was flushed with nitrogene while 2,4-dimethylthiazole (1.47 g, 12.7 mmol) was added. The tube was sealed and the mixture irradiated for 30 minutes at 170° C. The red-brown mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate. The combined organic phases were washed with water, with brine, dried with magnesium sulfate and the solvent was evaporated to dryness. Column chromatography (40 g silica, heptane/ethyl acetate 7:3 v/v) afforded the title compound (415 mg, 62%) as a yellow solid. MS ISP (m/e): 265.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.90 (dd, 1H), 7.81 (d, 1H), 7.45 (d, 1H), 3.95 (s, 3H), 2.71 (s, 3H), 2.35 (s, 3H). mp 123-125° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ncc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1NCCc2cc(Cl)ncc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 191.2 %

Procedure:
To a solution of tert-butyl 6-chloro-1-oxo-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (3.0 g, 10.6 mmol) in DCM (20 mL) was added 4N HCl solution in dioxane (10 mL). After stirring 20 minutes at room temperature, the reaction was diluted with DCM (50 mL, then sonicated and filtered to give 6-chloro-3,4-dihydro-2,7-naphthyridin-1(2H)-one hydrochloride (2.22 g, 93% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.70 (s, 1H), 8.23 (br. s., 1H), 7.57 (s, J=0.6 Hz, 1H), 3.40 (t, J=6.6, 2.8 Hz, 2H), 2.96 (t, J=6.6 Hz, 2H); MS (EI) m/z=183.6 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:16][CH2:15][CH2:14][C:13]2([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:9]1[C:10](=[O:34])[N:11]([C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1)[C:12]2=[O:25])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:13]23[C:12](=[O:25])[N:11]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:10](=[O:34])[N:9]2[NH:8][CH2:16][CH2:15][CH2:14]3)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2(Cc3ccc(Br)cc3)C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCNN12
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
2-(tert-Butoxycarbonyl)-6-(4-bromobenzyl)-8-(3,5-dichlorphenyl)-1,2,8-triazabicyclo[4.3.0]nonane-7,9-dione (260 mg) was dissolved in TFA/CH2Cl2 (50%, 5 mL) and stirred at room temperature for 3 hours. The reaction mixture was then concentrated in vacuo, redissolved in CH2Cl2 (5 mL) and DIEA (0.22 mL) was added. The mixture was stirred at room temperature for 30 minutes and was shaken with CH2Cl2/H2O. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was recrystallized from EtOAc/hexane to give the titled compound (180 mg). MS (m/z) 470 (M+).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:10][CH:11]3[C:19]4[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[NH2:23][C:24]1[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=1>>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH:11]([NH:10][C:7]1[O:8][CH2:9][C:4]3[CH:3]=[C:2]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][N:25]=4)[CH:22]=[CH:21][C:5]=3[N:6]=1)[CH2:12][CH2:13]2
Reactant: Fc1ccc2c(c1)CCC2NC1=Nc2ccc(Br)cc2CO1
Reactant: Nc1nccc(C(F)(F)F)n1
Product: Fc1ccc2c(c1)CCC2NC1=Nc2ccc(Nc3nccc(C(F)(F)F)n3)cc2CO1
Yield: 51 %

Procedure:
The title compound (113 mg, 51%), yellow foam, MS (ISP): m/e=444.2 (M+H+), was prepared in accordance with the general method of Example 35 from rac-(6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(5-fluoro-indan-1-yl)-amine (Example 53) (181 mg, 0.5 mmol) and commercially available 2-amino-4-trifluoromethyl-pyrimidine (163 mg, 1.0 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]([NH:47][C:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45](=[O:46])[NH:47][C:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 63 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(naphthalen-1-ylmethyl)-N4-tritylsuccinamide (Compound IV-19) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[CH3:34][N:35](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:34]([C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:35]
Reactant: CCOC(=O)c1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: O
Product: CCOC(=O)c1cc(F)ccc1C#N
Temperature: 130 °C
Reaction time: 4 h

Procedure:
Zinc cyanide (26.5 g; 0.225 mol) and Pd2(dba)3 (1.9 g; 3.4 mmol) were added to a solution of ethyl 2-bromo-5-fluorobenzoate (27.9 g; 0.112 mol) in DMF (71 ml). Triphenyl phosphine (2.9 g; 11 mmol) was added and then the reaction mixture was stirred at 130° C. under nitrogen atmosphere for 4 hours. The mixture was poured out into H2O (300 ml) and then extracted with EtOAc (200 ml). The organic layer was separated, washed with H2O (2×100 ml), brine (100 ml), dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH:2]2[C:7]([OH:9])=[O:8])(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: O=C(O)C1COCCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCOCC2C(=O)O)cc1

Procedure:
3-Morpholinecarboxylic acid is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 4-[(4-methoxyphenyl) sulfonyl]-3-morpholinecarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=O)[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[C:3](/[C:9](=[N:36]/[OH:37])/[CH2:10][C@H:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: Cc1ccccc1[C@H](CC(=O)c1cc(F)ncc1Cl)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1[C@H](C/C(=N\O)c1cc(F)ncc1Cl)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 132, step 6, from 4′-[(R)-3-(5-chloro-2-fluoro-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow oil, MS (ESI−): m/z=487.3 ([M−H]−).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)C.[ClH:29]>O1CCOCC1>[ClH:29].[N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:20]([F:23])([F:21])[F:22])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cnc(N2CCCC2)cc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Nc1cnc(N2CCCC2)cc1C(F)(F)F
Reaction time: 5 h

Procedure:
A solution of 1 g (3.02 mmol) of 6-(pyrrolidin-1-yl)-4-trifluoromethyl-3-(terbutoxycarbonylamino)pyridine, prepared in the preceding stage, in 11 mL of 4N hydrochloric acid in dioxane, is stirred for 5 hours under reflux. Then 200 mL of ethyl ether is added to the cooled reaction mixture. 0.8 g of a precipitate is collected by filtration.
Reaction SMILES: ClC(OCC)=O.[Br:7][C:8]([CH3:19])([CH3:18])[C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=O.C(N(CC)CC)C>CC(C)=O>[Br:7][C:8]([C:9]1[O:14][C:13](=[O:15])[C:12]([CH3:17])([CH3:16])[N:11]=1)([CH3:19])[CH3:18]
Reactant: CC(C)(Br)C(=O)NC(C)(C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(Br)C1=NC(C)(C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of ethyl chloroformate (32.4 g, 0.30 mol) in 50 mL acetone was added dropwise to a stirring mixture of 2-(2-bromo-2-methyl propionylamino)-2-methylpropionic acid (67.9 g, 0.27 mol) and triethylamine (30.0 g, 0.30 mol) in 200 mL of acetone at −15° C. When addition was complete, the mixture was stirred at room temperature for 2 hours, and the white solid was filtered off and washed with 100 mL of ether. The combined filtrates were reduced in volume to about 200 mL at reduced pressure and cooled in a refrigerator at about 5° C. overnight. The small amount of white solid that had separated was removed by filtration, and the solvents were evaporated at reduced pressure. The residue was taken up in 300 mL of ether, filtered, and the solvent evaporated to leave the title compound (61.5 g, 98%) with IR and NMR spectra consistent with the desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12]N(C)C)=[CH:6][CH:5]=1.Cl.[NH2:26][C:27]([NH2:29])=[NH:28].C[O-].[Na+]>CO>[CH3:24][O:23][CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][N:26]=[C:27]([NH2:29])[N:28]=2)=[CH:6][CH:5]=1
Reactant: COC(OC)c1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(-c2nc(N)ncc2-c2ccccc2)cc1

Procedure:
5 g of the product of step 3 and 3 g guanidine hydrochloride were dissolved in 100 mL methanol and 2.7 g of NaOMe was added. The mixture was heated to reflux for 17 h. The product was precipitated upon dilution of the mixture with water and was collected by filtration and washed twice with water.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cccc(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(F)c2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (68 mg, 0.20 mmol), (2,3-difluorophenyl)acetic acid (34.5 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol) in DMF (2 mL) was added Hunig's base (0.14 mL, 0.802 mmol). The mixture was stirred at room temperature overnight. LCMS showed reaction was completed. The reaction was poured into water, a white solid formed. The solid was filtered to give a white solid as the title compound. The final product has about 0.7 equivalent of DMF.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].C([O-])(=O)C.[Na+].C(O)(=O)C.[Br:18]Br>O>[Br:18][C:8]1[C:4]([N+:1]([O-:3])=[O:2])=[N:5][NH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
A 1 L 3-neck flask equipped with a stir bar was charged with 3-nitro-1H-pyrazole (41.3 g, 365 mmol), sodium acetate (36.0 g, 438 mmol), and acetic acid (260 mL). The flask was fitted with a septum, addition funnel, and a temperature probe. Bromine (23 mL, 450 mmol) was added over 30 minutes via addition funnel to the reaction mixture; the temperature increased to 40° C. over the course of bromine addition. The heterogeneous reaction mixture became homogeneous as the reaction progressed, with the exception of a few chunks of solid. As the temperature of the reaction mixture fell, a precipitate formed. The reaction mixture was poured into 1.2 L of ice and water and stirred vigorously. After 15 minutes, the solids were collected by filtration and washed with several portions of water (500 mL total). The solids were dried under vacuum to afford the product as a tan powder (49.67 g, 71%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][N:7]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:8]1([C:13](=[O:16])[NH:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)C.C1(C)C=CC=CC=1.O.[OH-].[Na+]>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:17]([N:7]([C:8]3([C:13](=[O:16])[NH:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:6][CH2:5][C:4]([OH:34])=[O:3])(=[O:19])=[O:18])=[CH:21][CH:22]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCN(C1(C(=O)NO)CCCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
A solution of 7.48 g (15.1 mmol) of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was concentrated by rotary evaporation with the addition of 75 mL of toluene. This solution was treated with 75 mL of water, cooled to 0° C., and treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets over 10 minutes with vigorous stirring. This mixture was stirred for 15 minutes at 0° C. and warmed to ambient temperature over one hour. The aqueous phase was separated, diluted with 7.5 mL of tetrahydrofuran, cooled to 0° C., and treated with 33 mL of 6N aqueous hydrochloric acid over 20 minutes. This mixture was stirred with 75 mL of ethyl acetate at 0° C. to ambient temperature, and the ethyl acetate phase was separated and washed with water. The ethyl acetate solution was slowly treated with 150 mL of hexanes at ambient temperature causing solids to precipitate, and was stirred overnight. Filtration yielded 5.01 g of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxy carbamoylcyclopentyl) amino]propionic acid as a white solid (71% yield from 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy) benzenesulfonyl]amino}cyclopentanecarboxylic acid).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:17])(=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O1COCO[CH2:19]1>O>[C:11]([C:10]1[CH:14]=[C:15]2[C:7](=[CH:8][CH:9]=1)[C:6](=[O:17])[O:16][CH2:19]2)([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: C1OCOCO1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 1 °C
Reaction time: 0.5 h
Yield: 104.4 %

Procedure:
To 153 ml of fuming sulfuric acid, containing 25% of SO3, 50 g (0.3 m) of terephthalic acid are added, in small portions, at 20-22° C., then to the mixture thus obtained 23 g (0.25 m) of 1,3,5-trioxane are added portionwise thereinto. The mixture is kept about 30 minutes under stirring, without cooling, then the temperature is brought to 135-140° C. and heating is continued for 2-2.5 hours, whereby the reaction is complete, as shown by a HPLC control. The reaction mixture is cooled to 0-2° C. and 1000 ml of cold water are added thereto without exceeding 20-23° C., by keeping in mind that, during the addition of the first 15-20 ml of water, exothermia occurs, whilst afterwards the temperature may be easily controlled. The mixture is kept 1 hour under stirring at 20-25° C., the product thus obtained is filtered, still moist triturated in 300 ml of water repeatedly until the reddish colour of the mother liquors disappears. After the third trituration, the pH of the mother liquors stabilizes at values ranging from 5 to 6. The product is dried in vacuo at 45-50° C. until constant weight to give 47.5 g of 5-carboxyphthalide with a titer and a purity (HPLC)>95%.