Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[C:4]1C=C[C:7]([NH:10][C:11]([N:13]2[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[CH:6][C:5]=1OC.[Li+].[OH-:45].[CH2:46]1[CH2:50][O:49][CH2:48][CH2:47]1>O>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:17][N:13]2[C:11]([NH:10][CH2:7][CH:6]2[CH2:5][CH2:4][CH:47]([C:48]([OH:45])=[O:49])[CH2:46][CH2:50]2)=[O:12])[CH:38]=[CH:37][CH:36]=1
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(NC(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Agent: [Li+]
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(C(=O)NCC2CCC(C(=O)O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a mixture of rac-4-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-2-methoxy-benzoic acid methyl ester (26.5 mg, 0.042 mmol, Example 70) in THF (2.4 mL) was added a solution of LiOH (Aldrich, 12.9 mg, 0.307 mmol) in water (1.2 mL) and the reaction mixture was stirred at rt for 16 hrs then more THF (3 mL) and water (1.5 mL) was added and stirred for 5 additional hrs at 50° C. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 5-7), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give rac-4-({[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-methyl)-cyclohexanecarboxylic acid (25.7 mg, 99.2%). HRMS (ES+) m/z Calcd for C31H29O2F2N3O4+H [(M+H)+]: 616.1576; Found: 616.1573.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:10](OCC)(OCC)OCC.C1(C)C(C)=CC=CC=1>C(OCC)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[N:9][N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1nccnc1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: Clc1nccn2cnnc12
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 1-(3-chloropyrazin-2-yl)hydrazine (0.90 g, 62 mmol), triethyl orthoformate (2.3 mL), 14 mmol), and dry xylene (15 mL) was refluxed with stirring for 2 h. The mixture was brought to RT, diethyl ether was added and the suspension was filtered. The solid collected was washed with diethyl ether to afford 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (0.60 g, 62% yield). MS m/z: 155.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[NH:8][C:7]([C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:11][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[C:7]1[C:9]#[N:10]
Reactant: N#Cc1ccc([N+](=O)[O-])[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1c(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of 300 mg of 5-nitropyrrole-2carbonitrile (2.14 mol) in 15 mL of acetone, 360 mg of potassium carbonate (2.6 mmol) and 0.65 mL of iodomethane (1.6 mmol, 372 mg) are added. The mixture is then stirred at room temperature for 24 hours. The reaction mixture is poured into ice-water (100 mL) and the precipitate which forms is collected to yield (200 mg), 62% mp 86°-87° C. of 1-methyl-5-nitropyrrole-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Li]CCCC.C1CCCCC1.[CH:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:27]=[C:28]([Cl:33])[CH:29]=[C:30](Cl)[N:31]=2)=[CH:24][CH:25]=1>C1COCC1.C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:33][C:28]1[N:27]=[C:26]([C:23]2[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=2)[N:31]=[C:30]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:29]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloroaniline (127.6 mg, 1 mmol) in dry THF (2 mL) was cooled in a dry-ice/acetone bath and treated dropwise with a solution of nBuLi in cyclohexane (0.5 mL, 2M, 1 mmol). The mixture was treated with additional dry THF (2 mL) and was allowed to warm slightly (˜15 minutes) till the material went into solution. The material was then transferred by cannula into a solution of fenclorim (XXII) (225 mg, 1 mmol) and bis(triphenylphosphine)palladium(II) dichloride (35 mg, 0.05 mmol) in dry THF (2 mL). Rinsed with dry THF (2 mL) and stirred at room temperature for 30 minutes. The reaction was partitioned between saturated sodium bicarbonate and ethyl acetate. Added brine to help clear an emulsion. Separated layers and the aqueous layer was extracted twice with ethyl acetate. The combined organics was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield a film. The film was taken up in chloroform and loaded onto 100 g of silica gel. The silica gel was eluted with 10% ethyl acetate/hexanes followed by 20% ethyl acetate/hexanes. The appropriate fractions were concentrated to yield 6-chloro-N-(4-chlorophenyl)-2-phenylpyrimidin-4-amine (XXIII) as a film (161.87 mg). ESI/MS 315.9, 317.9 (M+H), 314.0, 316.0 (M−H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[C:5]([NH2:12])=[N:4][CH:3]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:13](=[O:14])[NH:12][C:5]2=[N:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ncc(Br)nc1NC1CC1
Solvent: C1CCOC1
Product: O=c1[nH]c2ncc(Br)nc2n1C1CC1
Temperature: 66 °C
Yield: 56.7 %

Procedure:
To a heated (50° C.) solution of 6-bromo-N2-cyclopropylpyrazine-2,3-diamine (0.740 g, 3.23 mmol) in THF (20 mL) was added 1,1′-carbonyldiimidazole (1.00 g, 6.17 mmol) in one portion. The reaction was then heated at 66° C. for 3 h. Additional 1,1′-carbonyldiimidazole (1.00 g, 6.17 mmol) was added and the reaction was heated at 50° C. overnight. The reaction was cooled to room temperature and carefully quenched with water (slight exotherm) until gas evolution ceased. The solution was diluted with EtOAc and the layer were separated. The organic layer was washed with water (1×) and brine (1×). The solution was evaporated onto silica gel and purified by flash chromatography (ISCO(40 gram)) eluting with EtOAc:hexanes (0:1→2:3) to give 467 mg (57%) of a yellow crystalline solid. ESI MS 256.9 [M+1].
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[CH3:2][O:3][C:4](=[O:11])[CH:5]([N:6]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][CH2:8][S:9][CH3:10]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CCSC)N=Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
A suspension of methionine methyl ester hydrochloride (3.8 g, 19 mmol) and freshly distilled benzaldehyde (2 g, 19 mmol) in dichloromethane (60 mL) was cooled to 0° C. and magnetically stirred. A solution of triethylamine (1.92 g, 19 mmol) in solution in dichloromethane (30 mL) was added slowly thereto. The resulting solution was allowed to stand overnight at room temperature, with stirring. After removal of the solvent, the residue was taken up in anhydrous diethyl ether, with the insoluble material being filtered off. The filtrate was washed with water (3×30 mL), brine (2×40 mL), dried over sodium sulfate, and concentrated, to provide a crude material which was purified by distillation (bp 144° C., 4 mm) providing methyl-2-(benzylideneamino)-4-(methylthio)butyrate (3.62 g) at a yield of 76%.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CN(C)CCCCCC(=O)N1CCCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)CCCCCCN1CCCc2ccccc21

Procedure:
The 1-(6-dimethylaminohexanoyl)-1,2,3,4-tetrahydroquinoline (4.0 g) was added to a mixture of lithium aluminium hydride (1.4 g) and ether (200 ml). The mixture was refluxed for 5 hours, then cooled. Water was added cautiously, and the organic solution was separated, dried and evaporated to give the title compound as an oil which is then converted to the dihydrochloride, mp 116°-119°.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21]([Cl:27])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=3)[CH2:13][CH2:12]2)[N:7]=[C:6]([Cl:31])[CH:5]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[Cl:31][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[C:21]([Cl:27])=[C:20]([O:28][CH2:29][CH3:30])[CH:19]=3)[CH2:13][CH2:12]2)[N:7]=1)[C:3]([OH:32])=[O:2]
Reactant: CCOc1cc(CN2CCC(Nc3cc(C(=O)OC)cc(Cl)n3)CC2)cc(OCC)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(CN2CCC(Nc3cc(C(=O)O)cc(Cl)n3)CC2)cc(OCC)c1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
To a stirred solution of 2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinic acid methyl ester (0.17 g, 0.35 mmol, 1.0 equiv; example 224) in THF/methanol (2:1) (15 mL) was added a solution of 1 M LiOH (0.87 mL, 0.87 mmol. 2.5 equiv) drop by drop. After 16 h, the reaction mixture was poured into ice water, the pH of the water phase adjusted to 3-4 with diluted HCl and the mixture extracted twice with dichloromethane. The organic phases were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.12 g (73%) of the title compound as colorless solid. MS (ISP): 468.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:22]1([CH2:28][C:29]2[S:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:20][O:19][C:17](=[O:18])[C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:32]3[S:33][C:29]([CH2:28][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:30][CH:31]=3)[CH:6]=2)=[O:9])=[CH:16][CH:15]=[N:14][CH:13]=1
Reactant: COC(=O)c1cnccc1NC(=O)c1cc(Br)cnc1N
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Product: COC(=O)c1cnccc1NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)cnc1N

Procedure:
Reaction of methyl 4-[(2-amino-5-bromo-pyridine-3-carbonyl)amino]pyridine-3-carboxylate with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives compound “A35”; HPLC/MS: 1.36 min, [M+H]=454;
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[Cl:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:7][CH2:8][C@:4]([CH2:1][CH3:3])([OH:12])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2C)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (201 mg), 2-chloro-4-fluoro-3-methylbenzonitrile (294 mg) and lithium carbonate (250 mg), the title compound was obtained as pale-yellow oil (yield: 95.6 mg, yield: 31%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][CH:13]([CH2:16][N:17]=[N+:18]=[N-:19])[CH2:14]O.C(N(CC)CC)C>C(Cl)Cl.O>[OH:12][CH:13]([CH2:16][N:17]=[N+:18]=[N-:19])[CH3:14].[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O-:12])(=[O:3])=[O:2]
Reactant: [N-]=[N+]=NCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)CN=[N+]=[N-]
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
Tosyl chloride (2.3 g, 12 mmol) was added to a solution of 2-hydroxy-3-azido-propanol (1.17 g, 10 mmol) and triethyl amine (3.6 g, 36 mmol) in methylene chloride (50 ml) and was stirred at RT for 4 h. The reaction was diluted with water (20 ml), extracted with EtOAc (2×50 ml); the combined organic layers were extracted with pH 7 buffer (2×50 ml), then were dried with magnesium sulfate, filtered, concentrated in vacuo, and chromatographed (silica gel, 30% EtOAc/hexanes) to produce a white solid (1.2 g, 44%); MS(ES) M+H+=272.2. c) 2-(Merrifield polymer-6-(oxymethylene-tetrahydropyran-acetal)-3-azido-propan-tosylate
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1.[F-:17].[Cs+]>CS(C)=O.O>[F:17][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([F:12])[CH:10]=2)[C:5]([O:15][CH3:16])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cc2c(OC)cnc(Cl)c2cc1F
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(OC)cnc(F)c2cc1F
Temperature: 145 °C
Yield: 25.5 %

Procedure:
To a solution of 1-chloro-7-fluoro-4,6-dimethoxyisoquinoline (2 g, 8.28 mmol) in DMSO (5 ml) was added cesium fluoride (2.51 g, 16.55 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (475 mg, 25.5%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.69-7.67 (d, J=8 Hz, 1H), 7.53-7.51 (d, J=8 Hz, 1H), 7.45-7.44 (m, 1H), 4.05 (s, 3H), 4.03 (s, 3H); 19F NMR: δ ppm −129.58 (1F), −79.2 (1F); MS: MS m/z 226.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:31]4[CH2:36][CH2:35][S:34][CH2:33][CH2:32]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C1CSCCN1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCSCC1

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and thiomorpholine was converted to 48.1 mg of the title compound (free base), mass spectrum (electrospray, m/e): M+H 512.0 and 33.2 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 512.0.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:20]=[N:21][C:22]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH:24]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(OCc2cnc(-c3cc(OC)ccc3F)c(OCC(C)C)c2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ncc(COc3cc(C(CC(=O)O)C4CC4)ncn3)cc2OCC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-((6-(2-fluoro-5-methoxyphenyl)-5-isobutoxypyridin-3-yl)methoxy)pyrimidin-4-yl)propanoate (890 mg) in THF (5.0 mL) and methanol (2.5 mL) was added 1N aqueous sodium hydroxide solution (5.0 mL), and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid (5.0 mL) was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized (ethyl acetate/hexane) to give the title compound (688 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13](=O)[NH:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:18]>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13]([Cl:18])=[N:12][CH:11]=[N:10][C:9]=3[S:15][C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2sc3cc(Br)ccc3c12
Solvent: CCN(CC)CC
Product: Clc1ncnc2sc3cc(Br)ccc3c12
Yield: 91 %

Procedure:
7-Bromo[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (7.80 g, 27.7 mmol), POCl3 (70 mL) and triethylamine (70 mL) were heated in an oil bath at 80° C. for 3 h. The resulting slurry was concentrated on a rotavap, slurried in dichloromethane and poured into 500 mL of satd NaHCO3. The organic phase was then washed with satd NaHCO3, water, and then collected. The initial aqueous phase (pH<1) was basified with 1.0 N NaOH and extracted with dichloromethane. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated under high vacuum to yield a crude brown solid (7.6 g, 91%). 1H NMR (DMSO-d6) δ 9.05 (s, 1H), 8.60 (d, 1H), 8.60 (s, 1H), 7.88 (d, 1H).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].C([O-])([O-])=O.[K+].[K+].[CH:36]1(Br)[CH2:40]C[CH2:38][CH2:37]1>C(#N)C>[CH:17]1([N:14]2[CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:28])[C:8]4[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:29])[CH:7]=4)[O:24]3)[CH2:12][CH2:13]2)[CH2:38][CH2:37][CH2:36][CH2:40]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C3CCCC3)CC1)O2
Temperature: 75 °C
Yield: 95.1 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (500 mg, 1.48 mmol, Intermediate 1, hydrochloride salt) was suspended in acetonitrile (65 ml). K2CO3 (818 mg, 5.92 mmol) and cyclopentyl bromide (882 mg, 5.92 mmol) were subsequently added and the mixture was heated at 75° C. for 14 h. The solvent was then evaporated and the residue was diluted with water and extracted with ethyl acetate, which was dried and evaporated. The crude orange solid (540 mg) was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-cyclopentyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (500 mg) as a light brown solid. The acid was suspended in DCM (16 ml), TEA (0.30 ml) was added and the resulting clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-cyclopentyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as an orange solid (360 mg). The protected hydroxamic acid was dissolved in DCM (4 ml) and treated with 1 M HCl in diethyl ether (4 ml, 4 mmol) as described in Example 2, Step D, giving a light pink solid (247 mg, trifluoroacetate salt) after purification by preparative HPLC.
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12](O)=[O:13])[CH2:8][CH2:7]1)#[N:2].CN(C)C=O.S(Cl)([Cl:40])=O>O1CCCC1>[ClH:40].[C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([Cl:40])=[O:13])[CH2:8][CH2:7]1)#[N:2]
Reactant: N#CC(CCN1CCC(C(=O)O)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cl
Product: N#CC(CCN1CCC(C(=O)Cl)(c2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 7 grams of 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid suspended in 100 ml. of anhydrous tetrahydrofuran and 5 ml. of redistilled N,N-dimethylformamide is added 8 ml. of thionyl chloride in 50 ml. of anhydrous tetrahydrofuran. The resulting clear solution is stirred at room temperature under anhydrous conditions for about 5 minutes, then heated at the reflux temperature for 15 minutes and concentrated to dryness. To the residue is added an equal volume of tetrahydrofuran and the resultant mixture is contacted with a stream of nitrogen and stripped of solvent by vacuum distillation. The residue is triturated with cold tetrahydrofuran, then filtered. The filtrate is concentrated to dryness at room temperature in a nitrogen atmosphere. The solid residue is filtered with anhydrous ether and dried at room temperature in vacuo, thus affording 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylic acid chloride hydrochloride, melting at about 169°-171°C. with decomposition. The product has the formula ##SPC10##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([C@@H:10]1[CH2:13][CH2:12][N:11]1C(OC(C)(C)C)=O)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([C@@H:10]1[CH2:13][CH2:12][NH:11]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)Nc1cnccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cnccn1)[C@@H]1CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-tert-butyl 2-(pyrazin-2-ylcarbamoyl)azetidine-1-carboxylate (1.05 g, 3.77 mmol) in CH2Cl2 (40 mL) was added TFA (1.453 mL, 18.86 mmol). The reaction mixture was stirred at RT overnight and concentrated. The residue was used for the next step without purification. LC/MS [M+H]+: 179; Ret time (Method F): 0.29 min.