Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[C:17]([N:25]3[CH2:30][CH2:29][NH:28][C@@H:27]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26]3)[CH:18]=[CH:19][C:20]=2[O:21][CH:22]([F:24])[F:23])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][O:14][C:15]2[CH:16]=[C:17]([N:25]3[CH2:30][CH2:29][N:28]([C:7](=[O:9])[CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[C@@H:27]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26]3)[CH:18]=[CH:19][C:20]=2[O:21][CH:22]([F:23])[F:24])[CH2:12][CH2:11]1
Reactant: CC(C)C[C@H]1CN(c2ccc(OC(F)F)c(OCC3CC3)c2)CCN1
Reactant: O=C(O)Cc1c[nH]cn1
Product: CC(C)C[C@H]1CN(c2ccc(OC(F)F)c(OCC3CC3)c2)CCN1C(=O)Cc1c[nH]cn1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-3-isobutyl-piperazine (Example 37, Compound 125) as starting materials. Product as an off-white solid (14%). LC/MS (Method B) 2.94 min, [M+1]+ 463.0. Potency class B.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[C:9]([Cl:11])[CH:8]=[N:7]1.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:9]1[CH:8]=[N:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:21]2[CH2:22][CH2:23][N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:19][CH2:20]2)[CH:10]=1
Reactant: Clc1cnn(CCCCBr)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cnn(CCCCN2CCN(c3ccccc3)CC2)c1

Procedure:
A mixture of 3.56 g (15 mmol) of N-(4-bromobutyl)-4-chloropyrazole, 2.43 g (15 mmol) of 1-phenyl-piperazine and 2.76 g (20 mmol) of potassium carbonate in 50 ml of dimethylformamide is refluxed for 24 hours. The reaction mixture is evaporated under vacuum, chloroform is added, the mixture is washed with water, dried over sodium sulphate and evaporated under vacuum and 3.1 g of 4-chloro-1-[4-(4-phenyl-1-piperazinyl)-butyl]-1H-pyrazole are obtained, which may be recrystallised from ethyl ether with a melting point of 58°-61° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]>>[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)\[CH3:18])=[CH:33][CH:34]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]
Reactant: C/C(=C\CO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(F)cc3)cc2)cc1)OCC
Yield: 89.1 %

Procedure:
The title compound (849 mg, 89%) was prepared as a colourless gum from (E)-3-(4′-fluoro-biphenyl-4-yl)-but-2-en-1-ol (500 mg, 2.06 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (516 mg, 2.17 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:15])[CH3:14])[C:6]=2[N:7]=1.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:13]([CH3:14])[CH3:15])[C:6]=2[N:7]=1
Reactant: CCc1nn(C(C)C)c2nc(Br)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Product: CCc1nn(C(C)C)c2nc(Br)cc(C(=O)NCc3c(C)cc(C)[nH]c3=O)c12
Reaction time: 12 h
Yield: 87 %

Procedure:
A solution of 6-bromo-3-ethyl-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.3 g, 0.901 mmol) and 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.292 g, 1.92 mmol) in DMSO (4 mL) and was stirred at room temperature for 15 min. Then PyBOP (0.75 g, 1.44 mmol) was added to it and stirring was continued for 12 hr. After completion of the reaction, reaction mass was poured into ice to obtain solid, which was filtered and washed with acetonitrile followed by ether to provide the desired intermediate (0.35 g, 81.6%).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:7][N:8]=1.[CH2:18]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH2:18]([O:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:7][N:8]=2)=[O:34])=[CH:36][CH:37]=1)/[CH:19]=[C:20](/[CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])\[CH3:21]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reactant: Nc1nnc(SCCN2CCCCC2)s1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)Nc2nnc(SCCN3CCCCC3)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
Sodium hydride (0.4 g) and 2-amino-5-piperidinoethylthio-1,3,4-thiadiazole (1.5 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Geranyloxybenzoic acid (1.6 g) and carbonyldiimidazole (1.1 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.3 g of the aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:14][C:15](=[O:18])[CH2:16]Cl)([CH2:12][OH:13])[CH2:10][OH:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC(C)([O-])C.[K+].O>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:12][OH:13])[NH:14][C:15](=[O:18])[CH2:16][O:11][CH2:10]2)[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=C(CCl)NC(CO)(CO)c1cc(Br)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1COCC(CO)(c2cc(Br)cnc2Cl)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of N-[1-(5-bromo-2-chloro-pyridin-3-yl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide (622 mg, 1.74 mmol) in tert.-butanol (10.2 ml) was added at 0° C. potassium tert.-butoxide (292 mg, 2.61 mmol), the reaction mixture was stirred at room temperature for 1 h. Water was added and the tert.-butanol evaporated, the mixture was extracted with EtOAc, the combined organic layers were washed with halfsaturated aq. NaCl, dried with Na2SO4 and evaporated to provide the title compound as beige foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:15])[OH:14])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[I:21]Cl.O>C(O)(=O)C>[I:21][C:6]1[C:7]2[S:11][C:10]([NH:12][C:13](=[O:14])[OH:15])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: ClI
Reactant: COc1cccc2sc(NC(=O)O)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(I)c2sc(NC(=O)O)nc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(4-Methoxy-benzothiazol-2-yl)-carbamic acid methyll ester (31.0 g, 130 mmol) and sodium acetate (32.3 g, 394 mmol) are dissolved in 400 ml of glacial acetic acid and slowly treated with iodine monochloride (13.5 ml, 264 mmol) at 0° C. The reaction mixture is then slowly warmed to room temperature and stirred for 15 hours. After addition of water (1.31), the formed precipitate is filtered off and washed with water. The filter cake is then dissolved in a minimal amount of tetrahydroflirane (about 150 ml) and decolorized with 1M aqueous sodium thiosulfate. The product is precipitated by the addition of water (about 2.01), filtered off and dried at 60° C. for 12 hours. 42.3 g (89%) white solid. MS: m/e=364 (M+).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6](=[N:11][OH:12])[C:7]([F:10])([F:9])[F:8]>CO>[F:8][C:7]([F:10])([F:9])[C:6]1[CH:5]=[C:1]([NH2:2])[O:12][N:11]=1
Reactant: [C-]#N
Reactant: ON=C(CBr)C(F)(F)F
Agent: [K+]
Solvent: CO
Product: Nc1cc(C(F)(F)F)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a suspension of KCN (1.90 g, 29.1 mmol) in MeOH (35 mL) was added dropwisely 3-bromo-1,1,1-trifluoropropan-2-one oxime (5.00 g, 24.3 mmol) in MeOH (72 mL) at RT. The reaction mixture was stirred at RT for 3 hours. The solution was evaporated and then the residue was dissolved in EtOAc and stirred at RT. The solid was filtered and the filtrate was evaporated to obtain the crude product. The crude product was purified by silica gel column chromatography (Biotage: 25M, 10% to 60% EtOAc/hexane: 550 mL) to obtain 3-(trifluoromethyl)isoxazol-5-amine (1.38 g, 37% yield). MS (ESI) m/z: 153.0 (M+H+).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH2:13][NH2:14]>CO>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([NH:13][NH2:14])=[O:2])=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: CO
Product: NNC(=O)Cc1ccc(O)cc1
Temperature: 55 °C
Yield: 86 %

Procedure:
To a solution of (4-Hydroxy-phenyl)-acetic acid methyl ester (5 g, 30.08 mmol) in MeOH (20 mL, anhydrous) was added hydrazine (3.77 mL, 120.35 mmol) and then heated to 55° C. for 1 hour. A white precipitate formed during heating. The reaction was then cooled to rt and stirred for an additional hour to facilitate precipitation of solid. The reaction was filtered and the solid was washed with MeOH and dried resulting in the desired product (4.3 g, 86%) as a white solid. 1H-NMR (DMSO): δ 9.20 (1H, s), 9.10 (1H, s), 7.04-7.02 (2H, d, J=8.6 Hz), 6.67-6.65 (2H, d, J=8.6 Hz), 4.17-4.16 (2H, s), 4.11-4.09 (1H, q, J=5.0, 5.5 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Sn].Cl>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Agent: [Sn]
Product: Cc1ccc(N)cc1C(=O)O
Yield: 75 %

Procedure:
The desired titled compound was prepared by reducing 2-methyl-5-nitrobenzoic acid using a tin/hydrochloric acid mixture (m.p. 142°-144° C.). Yield: 75%
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)[C:11]2=[O:21])=[CH:6][CH:5]=1.C([Li])CCC.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37]>C1COCC1>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:21])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:15][C:16]1=[O:20])(=[O:38])=[O:37]
Reactant: O=C1CC2(CCN1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1CC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CCN1S(=O)(=O)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 31.7 %

Procedure:
2-(4-Trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-1,7-dione (0.105 g), product of example 1 step D), was dissolved in dry THF (10 ml), cooled to −78° C. under an argon atmosphere, treated dropwise with n-butyllithium (1.6 molar solution in hexanes, 0.22 ml) and then stirred for 20 minutes at −78° C. 2-Chlorobenzenesulfonyl chloride (0.074 g) in THF (2 ml) was then added dropwise, the mixture was stirred 15 minutes at −78° C., the cooling bath was removed and stirring was continued for further 75 minutes, allowing the temperature of the reaction mixture to rise to RT. The reaction mixture was then concentrated in vacuo, the residue adsorbed on silica gel and chromatographed on silica gel (AcOEt/heptane, gradient from 0 to 30%) to give the desired product (0.051 g) as an off-white solid. MS (ESI): 503.0 (MH−).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][C@@H:8]([CH2:15][N:28]=[N+:29]=[N-:30])[CH2:9][C@H:10]([CH3:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCC[C@@H](C)C[C@H](CN=[N+]=[N-])CC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 78.3 %

Procedure:
Tosylate 104 (2.92 g, 7.3 mmol) and sodium azide (1.43 g, 0.02 mol) were warmed to ˜50° C. in DMSO (30 mL). After 2 hours the solution was cooled to room temperature and diluted with water. The solution was extracted with ether and the combined organic phases dried (MgSO4) and concentrated to give an oil 1.54 g, 79%. Further purification by flash chromatography (95% hexane/EtOAc) gave an oil. [α]D=−8.3 (c 1 in CHCl3). 13C NMR (100 MHz; CDCl3) 172.01, 80.73, 54.89, 39.73, 39.46, 39.00, 33.40, 29.85, 28.30, 20.15, 19.82, 14.52.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36]([CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[C:15]3[CH:44]=[CH:45][CH:46]=[CH:47][C:14]1=3)=[C:7]([O:48][CH3:49])[CH:6]=[CH:5]2.[ClH:50]>CO.C(OCC)C>[ClH:50].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36]([CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:37])[C:15]3[CH:44]=[CH:45][CH:46]=[CH:47][C:14]1=3)=[C:7]([O:48][CH3:49])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)C2CCOCC2)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3cc(Br)ccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C
Reaction time: 3.5 h
Yield: 86 %

Procedure:
A solution of tert-butyl(S)-1-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55 mg, 75 μmol) in methanol (500 μl) at room temperature was treated with a 2 M hydrochloric acid in diethyl ether solution (1.3 ml) and stirred for 3.5 h. The reaction was then concentrated in vacuo, dissolved in water and placed on a lyophilizer over night to afford (S)-N-((3S,4S)-1-((6-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (43 mg, 86%) as an off white powder: LC-MS m/z 637 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[CH3:25])=[N:5][C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=1)[CH3:2].C(O)C>[Pd].O1CCCC1>[NH2:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][C:4]1[N:5]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:15][C:14]=2[CH3:25])[C:7]([C:9]([NH2:11])=[O:10])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)cc2C)nc1Oc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)cc2C)nc1Oc1cccc(N)c1
Reaction time: 5 h
Yield: 99.3 %

Procedure:
To a mixture of 6-ethyl-3-{[2-methyl-4-(morpholin-4-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (145 mg), ethanol (2 mL), and tetrahydrofuran (6 mL) was added 10% palladium-supported carbon (50% wet product) (30 mg), followed by stirring for 5 hours under a hydrogen gas atmosphere (1 atm). The reaction mixture was filtered through celite and then the solvent was evaporated under reduced pressure to obtain 5-(3-aminophenoxy)-6-ethyl-3-{[2-methyl-4-(morpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide (135 mg) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19](F)[CH:18]=2)[N:3]=1.O.[NH2:27][NH2:28]>C(O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]2[C:14]([NH2:16])=[O:15])[CH:5]=[C:4]([C:17]2[CH:18]=[C:19]3[C:20]([C:23]([NH2:24])=[N:27][NH:28]3)=[CH:21][CH:22]=2)[N:3]=1
Reactant: NN
Reactant: N#Cc1ccc(-c2cc(N3CCOCC3C(N)=O)nc(N)n2)cc1F
Solvent: CCO
Solvent: O
Product: NC(=O)C1COCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 90 °C
Reaction time: 16 h
Yield: 10.8 %

Procedure:
A mixture of 4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-morpholinecarboxamide (360 mg, 1.05 mmol) and hydrazine monohydrate (2.58 mL, 52.6 mmol) in ethanol (10 mL) was stirred at 90° C. in a sealed tube for 16 hours. The mixture was cooled and diluted with water. Attempts to extract the product from the water using 90/10 CH2Cl2/IPA were unsuccessful, so the aqueous phase was combined with the residue from the concentrated CH2Cl2/IPA extractions and the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (68 g SiO2, CHCl3 to 80/20/2 CHCl3/CH3OH/NH4OH gradient with a 10 minute hold at 90/10/1 CHCl3/CH3OH/NH4OH) to give the title compound (40 mg) as an off-white solid. LC-MS (ES) m/z=355 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.29-3.41 (m, 1H), 3.41-3.50 (m, 1H), 3.61 (dd, J=11.6, 3.5 Hz, 1H), 3.85-3.93 (m, 1H), 3.99-4.18 (bs, 1H), 4.35 (d, J=11.6 Hz, 1H), 4.82-5.08 (bs, 1H), 5.39 (s, 2H), 6.12 (s, 2H), 6.55 (s, 1H), 7.19 (s, 1H), 7.35 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.95 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.Cl.[N:13]1([C@H:18]2[CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[N:13]1([C@H:18]2[CH2:22][CH2:21][N:20]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:8])[CH2:19]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCN([C@H]2CCNC2)C1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-fluorobenzoic acid (3.5 g, 24.98 mmol) in DMF is treated with (S)-1,3′-bipyrrolidine dihydrochloride (10.65 g, 49.96 mmol), triethylamine (12.64 g, 124.90 mmol), 1-ethyl-3(3-dimethylaminopropyl)carbodiimide (5.75 g, 28.98 mmol) and N-hydroxybenzotriazole (4.05 g, 29.98 mmol), stirred at room temperature for 16 h and concentrated in vacuo. The resultant residue is partioned between CH2Cl2 and H2O. The organic phase is separated, washed sequentially with saturated NaHCO3 and brine, dried over MgSO4 and concentrated. The concentrate is absorbed onto silica and purified by flash column chromatography (10% methanol in CH2Cl2) to give the title product, identified by NMR and mass spectral analyses.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:7][C:6]3[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH3:13])=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=3)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(Cl)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-chloro-2-oxindole to give 0.3 g of 6-chloro-3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[O:21]1[C:25]2([CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:27]3[CH2:28][CH2:29][C:25]4([O:21][CH2:22][CH2:23][CH2:24]4)[CH2:26]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: C1COC2(C1)CCNC2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC2(CCCO2)C1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 1-oxa-7-azaspiro[4.4]nonane (176-12-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=394.5 [MH+].
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[C:11](Cl)(Cl)=[O:12]>>[Br:1][C:2]1[C:3]([N:10]=[C:11]=[O:12])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(N)n1
Reactant: O=C(Cl)Cl
Product: COc1ccc(Br)c(N=C=O)n1

Procedure:
3-Bromo-2-isocyanato-6-methoxy-pyridine was prepared by reaction of 3-bromo-6-methoxy-pyridin-2-ylamine with phosgene using the procedure of step 2 of Example 1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])[CH2:37][C:38](=O)[CH3:39])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:41])/[CH:37]=[C:38](\[NH:1][C@@H:2]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])=[CH:9][CH:8]=2)[C:3]([OH:5])=[O:4])/[CH3:39])=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)CC(C)=O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: COc1ccc(C(=O)/C=C(/C)N[C@@H](Cc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 52 mg (0.27 mmol) of Intermediate 22 to yield 126 mg of Example 41. TLC (EtOAc/MeOH (7:3): Rf=0.44: 1H NMR (DMSO-d6, 400 MHz) δ11.30 (d, 1H, J=7.00), 7.87 (m. 2H), 7.73 (d, 2H, J=8.72), 7.45 (m, 3H), 7.10 (d, 2H, J=8.37), 6.88 (d, 2H, J=8.89), 6.77 (d, 2H, J=8.37), 5.74 (s, 1H), 4.11 (m, 2H), 4.01(m, br, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.72 (m, 1H), 2.31 (s, 3H), 1.65 (s, 3H); low resolution MS (ES−) m/e 539 (M-H); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 10-50% CH3CN in H2O) with 0.1% HCO2H buffer: 30 minutes