Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:34])[C:18]2[N:17]=[C:16]([C:19](O)=[O:20])[CH:15]=[CH:14][C:13]=2[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:34])[C:18]2[N:17]=[C:16]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:15]=[CH:14][C:13]=2[NH:12][CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)[CH2:10]1
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)O)nc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2ccc(C(=O)NS(C)(=O)=O)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (267.5 mg, 6.9 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (0.66 g, 6.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A80. A solution of 8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (256.9 mg, 0.7 mmol) and 1,1′-carbonyldiimidazole (221.0 mg, 1.4 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B80. Solution B80 was added to Solution A80 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[8,8-dimethyl-6-(3-morpholin-4-yl-phenyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carbonyl]-methanesulfonamide (93.2 mg, 30%) as a white solid: MS (ESI) M+1=445.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]([CH3:24])=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:5])[CH3:2].[Na].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][C:9]([CH3:24])=[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:27][CH:29]2[O:31][CH2:30]2)=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: ClCC1CO1
Reactant: CCOC(=O)c1c(C)nc(C)c(C(=O)OCC)c1-c1ccc(O)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(C)c(C(=O)OCC)c1-c1ccc(OCC2CO2)cc1

Procedure:
9.0 g of the resulting 2,6-dimethyl-4-(4-hydroxyphenyl)-pyridine-3,5-dicarboxylic acid diethyl ester are dissolved in a solution prepared from 0.723 g of sodium metal and 80 ml of ethanol. This solution is slowly added drop-wise to a boiling solution of 11.9 ml of epichlorohydrin in 80 ml of ethanol; after cooling, the sodium chloride that is deposited is filtered off with suction and the filtrate is concentrated to dryness by evaporation. The residue is dissolved in ether and washed in succession with aqueous 1N sodium hydroxide solution, 1N hydrochloric acid, saturated aqueous potassium bicarbonate solution and finally with water. After distilling off the ether, the crude 2,6-dimethyl-4-[4-(2,3-epoxypropoxy)-phenyl]-pyridine-3,5-dicarboxylic acid diethyl ester is obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)=[N:10][N:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:34]([NH:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH3:35]>O1CCCC1>[CH2:34]([N:36]([CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[C:16](=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:8]=[N:9][N:10]=1)[CH3:35]
Reactant: O=C(O)CCCCc1nnnn1C1CCCCC1
Reactant: CCNC1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(C(=O)CCCCc1nnnn1C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
5-(1-Cyclohexyl-1,2,3,4-tetrazol-5-yl)valeric acid (2.4 g) is dissolved in tetrahydrofuran (50 ml), and thereto is added triethylamine (1.1 g). To the mixture is added dropwise with stirring isobutyl chloroformate (1.5 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the mixture is added dropwise with stirring N-ethyl-cyclohexylamine (1.5 g) at room temperature, and the mixture is further stirred for 2 hours. After distilling off tetrahydrofuran, water is added to the residue, and the mixture is extracted with chloroform. The chloroform layer is washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off, and the resulting residue is subjected to column chromatography (Kieselgel 60, made by Merck & Co., eluting solvent, chloroform) to isolate N-ethyl-N-cyclohexyl-5-(1-cyclohexyl-1,2,3,4-tetrazol-5-yl)valeramide (2.6 g), white crystalline powder (ether), m.p. 92°-95° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)[S:27][CH:28]=3)[N:17]=[C:16]([NH2:36])[C:15]=2[C:37]#[N:38])[CH2:10][CH2:9]1)(=O)C.[OH-].[Li+]>O1CCOCC1.O>[NH2:36][C:16]1[C:15]([C:37]#[N:38])=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][OH:4])[CH2:9][CH2:10]2)[C:19]([C:20]#[N:21])=[C:18]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:17]=1
Reactant: CC(=O)OCCCN1CCC(c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1C1CCN(CCCO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
65 mg (0.12 mmol) of the compound from Example 10 are initially charged in a mixture of 3.5 ml of dioxane and 1.7 ml of water, and 11 mg of lithium hydroxide are added. The mixture is initially stirred at RT for 8 h. Another 22 mg of lithium hydroxide are then added, and the mixture is stirred at RT for a further 16 h. The solvent is then removed on a rotary evaporator. The residue is taken up in 10 ml ethyl acetate and washed once with 3 ml of saturated aqueous sodium bicarbonate solution. The mixture is dried over magnesium sulfate. After removal of the solvent on a rotary evaporator the residue is purified chromatographically on silica gel 60 (mobile phase: gradient dichloromethane/ethanol 50:1→10:1).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14]O)=[NH:4].N[N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:19]=[C:18]1[NH2:29]>Cl>[ClH:28].[ClH:28].[OH:1][NH:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:14][N:17]1[CH:21]=[C:20]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:19]=[C:18]1[NH2:29])=[NH:4]
Reactant: Nc1nc(-c2ccc(Cl)cc2)cn1N
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Agent: Cl
Product: N=C(NO)c1cccc2c1CCC2=Nn1cc(-c2ccc(Cl)cc2)nc1N
Temperature: 120 °C

Procedure:
A mixture of 1.026 g (5 mmol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 1.043 g (5 mmol) of 1,2-diamino-4-(4-chlorophenyl)-imidazole (see Beyer H. et al., Chem. Ber. 101, 3151 (1968)) and 20 ml of 4N hydrochloric acid is heated at 120° C. for 18 hours, with stirring, and is then concentrated by evaporation in vacuo. 25 ml of ethanol are added to the crystalline residue, the mixture is cooled to 5° C., with stirring, and is filtered, and the crystallizate is washed with a small amount of ethanol and diethyl ether. The crude title compound, dried under a high vacuum, contains 8.17% water and melts at 226°-228° C. (decomp.), 1H-NMR (D2O): δ=8.06 (d, 1H); 7.75 (d, 1H); 7.55 (t, 1H); 7.40 (s, 1H); 7.38 (d, 2H); 7.28 (d, 2H); 3.21-3.27 (m, 2H), 3.03-3.09 (m, 2H).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16](Br)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:20]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)#[CH:21].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Pd](Cl)Cl>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16]([C:21]#[C:20][C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 2.0 g of 2-pivaloylamino-4-hydroxy-6-bromopyrido[2,3-d]pyrimidine (prepared according to Example 6), 1.31 g of tert.-butyl 4-ethynylbenzoate, 2.57 ml of triethylamine, 0.11 g of palladium chloride, 0.32 g of triphenylphosphine, and 0.05 g of cuprous iodide in 150 ml of acetonitrile is heated at reflux under nitrogen for 2.5 hours. The reaction mixture is cooled to room temperature and then in an ice bath. The solid is collected and washed with small portions of cold acetonitrile to yield 1.91 g (69%) of 2-pivaloylamino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine as a pale yellowish powder, which is sufficiently pure for the next reaction. A small sample of this solid, purified further by chromatography on silica gel using a 5% methanol:methylene chloride mixture as the eluent, had the following constants: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.37 (s, 9H), 1.63 (s, 9H), 7.61 (d, 2H, J=8.50 Hz), 8.02 (d, 2H, J=8.50 Hz), 8.42 (brs, 1H), 8.66 (slightly brs, 9.01 (slightly brs, 1H); IR (KBr) 3200, 2980, 1710, 1670, 1600, 1545, 1440, 1375, 1290, 1140, and 770 cm-1.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[C:11](Cl)(=[O:18])[C:12]1C=CC=CC=1>ClCCl>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:12])=[O:18])=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(C)=O)cc1
Reaction time: 16 h

Procedure:
4-Aminoacetophenone (1.35 g, 10.0 mmol) was dissolved in dichloromethane (10 mL) and treated with benzoyl chloride (1.74 mL, 15.0 mmol). The mixture was stirred for 16 hours at which time a white precipitate had formed. The solid was removed by filtration, washing with dichloromethane (3×20 mL) to provide 4-acetamidoacetophenone as a white sold (2.74 g). 1H NMR (200 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.92 (s, 7H), 7.54 (m, 3H), 2.50 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:39]1[CH:43]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[NH:41][N:40]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:33][O:32][C:5]1[CH:4]=[N:3][C:2]([C:39]2[CH:43]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[NH:41][N:40]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12](=[O:13])[N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)[C:6]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)[nH]n1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 120 °C

Procedure:
To a suspension of 1-(7-chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (2.50 g, 5.35 mmol) in 1,4-dioxane (60 mL) in a sealable flask was added ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (2.30 g, 5.36 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (1.86 g, 1.61 mmol). The mixture was flushed with N2, the flask was sealed, and the mixture was heated to 120° C. for 16 hr. The mixture was cooled to rt and diluted with MeOH (50 mL). The remaining solids were removed by filtering the mixture through a pad of celite and were washed with MeOH (25 mL). The remaining solvent was concentrated under reduced pressure. The resulting residue was dissolved in MeOH, and loaded onto a silica gel. After the silica was dry, a column was run using the biotage system with a 0 to 10% MeOH in CH2Cl2 gradient. After concentrating the desired fractions, 1.05 g of ethyl 3-(4-methoxy-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate was recovered as an orange solid. LCMS: m/e 571.2 (M+H)+, ret time 2.01 min (method 2). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.39-12.72 (m, 1 H) 8.37 (s, 1 H) 8.11 (s, 1 H) 7.52-7.76 (m, 6 H) 4.68-4.85 (m, 1 H) 4.38 (q, J=7.02 Hz, 2 H) 3.98-4.06 (m, 3 H) 3.67-3.73 (m, 2 H) 3.43-3.49 (m, 2 H) 3.28-3.36 (m, 2 H) 3.14-3.22 (m, 2 H) 1.36 (t, J=7.17 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]#[N:11].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]#[N:11])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: N#CCCc1ccccc1N
Product: N#CCCc1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-propionitrile was prepared from 3-(2-Amino-phenyl)-propionitrile and 2,4,5-Trichloro-pyrimidine in an analogous manner to Example 1230a. Title product was isolated as an off white solid (554 mg, 94%), MP: 115-116, LCMS 293.10 (M+H), HPLC purity: 92%, 1H-NMR (CDCl3, 400 MHz) δ:8.24 (s, 1H), 7.48-7.45 (m, 1H), 7.39-7.36 (m, 3H), 7.19 (bs, 1H), 2.98 (t, J=7.2 Hz, 2H), 2.71 (t, J=7.2 Hz, 2H).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12.Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]2[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=1.C(Cl)Cl>CN(C=O)C>[N:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][CH2:13][O:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][C:24]=3[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]4[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[CH:35])[CH:29]=3)[CH2:6][C:5]=12
Reactant: c1nnc2n1CCNC2
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCCl)cc23)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCCN4CCn5cnnc5C4)cc23)c1
Temperature: 80 °C
Reaction time: 36 h
Yield: 20.5 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.17 g) in DMF (8 mL) was added Ag2CO3 (1.29 g) and a solution of 6-(3-chloropropoxy)-N-(3-ethynylphenyl)-7-methoxyquinazolin-4-amine (0.45 g) in DMF (2 mL) at room temperature under stirring. The mixture was stirred at 80° C. for 36 h under N2 and cooled to room temperature. To this, CH2Cl2 (100 mL) was added. The mixture was washed with brine (100 mL×3), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to give the product (114 mg, 20.50%), HPLC: 90.63%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 456.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.03-2.10 (m, 2H), 2.68 (t, J=13.20 Hz, 2H), 3.03 (t, J=10.80 Hz, 2H), 3.75 (s, 2H), 3.89 (s, 3H), 3.99 (s, 1H), 4.03 (t, J=10.80 Hz, 2H), 4.08 (t, J=12.40 Hz, 2H), 7.03 (m, 1H), 7.24 (s, 1H), 7.32 (m, 1H), 7.38 (s, 1H), 7.81-7.84 (m, 2H), 8.46 (s, 1H), 8.70 (s, 1H) ppm.
Reaction SMILES: B.C1COCC1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=O)[CH2:23]2)[CH2:17][CH2:16]1>C1COCC1>[CH2:28]([N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([CH2:21][N:18]2[CH2:17][CH2:16][N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH3:7])[CH2:20][CH2:19]2)[CH2:23]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccccc1N1CCN(CC2CCCN(C(=O)c3ccccc3)C2)CC1
Agent: B
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CC2CCCN(Cc3ccccc3)C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
Borane-THF (1.0M, 5 mmol) was added dropwise to a THF solution (8 mL) of {3-[4-(2-methoxyphenyl)-piperazin-1-ylmethyl]-piperidin-1-yl}-phenyl-methanone (0.54 g, 1.37 mmol) from example 8 at 0° C. under nitrogen. The mixture was refluxed for 16 hours and after cooling to 0° C., the reaction was terminated by the addition of 2N-HCl (50 mL). After stirring for 1 hour, the solution was made basic with NaOH and the product extracted into ethyl acetate (3×35 mL). The combined organics were washed with water (50(mL), brine (50(mL) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuum gave the required product (0.36 g, 69% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (2.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.O>CC(C)=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:1][C:2]2[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(O)c(CC(C)C)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reaction time: 4 h
Yield: 88.5 %

Procedure:
Ethyl 4-hydroxy-3-isobutylbenzoate (25.6 g), potassium carbonate (31.8 g), and 4-fluorobenzyl bromide (26.1 g) were refluxed in acetone (150 ml) with stirring for 4 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum. The resulting residue, with water (50 ml), potassium hydroxide (12.9 g), and ethanol (100 ml) added thereto, was refluxed with stirring for 2 hours. The reaction mixture, with water added thereto, was neutralized with hydrochloric acid and then extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid and water successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained solid was recrystallized (from n-hexane/ethanol), thereby yielding 30.8 g of the aimed compound.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:15]([C:26]([O:28][CH2:29][CH2:30][C:31]#[N:32])=[O:27])=[C:14]([CH3:33])[NH:13][C:12]=1[CH3:34])=[O:10])C1C=CC=CC=1.C(O)=O>C(Cl)(Cl)Cl.[Pd]>[C:31]([CH2:30][CH2:29][O:28][C:26]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:34])[NH:13][C:14]=1[CH3:33])=[O:27])#[N:32]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(C)N1
Agent: [Pd]
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: CC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
A solution of 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine (3.24 g, 7.02 mmol) in 160 ml of 4.4%(w/w) formic acid/NeOH mixture was stirred with Pd/C (10%, 3.24 g) for 30 min., the reaction was quenched by addition of 10 ml of CHCl3. The mixture was filtered and concentrated to give a yellow powder, which was dissolved in CHCl3 (100 ml), washed with water (25 ml) and aqueous 1N HCl (25 ml). After drying (Na2SO4) and evaporation of solvent, 3-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid was obtained as a yellow powder (1.94 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)[CH:6]=[N:7][CH:8]=1.[ClH:19]>C(O)(C)C.O1CCOCC1>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[N:7][CH:8]=1
Reactant: COc1cncc(CCNC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1cncc(CCN)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of tert-butyl (2-(5-methoxypyridin-3-yl)ethyl)carbamate (153 mg, 0.606 mmol) in isopropanol (2 mL) was added 4M HCl in dioxane (2 mL) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated, the residual solid was washed with diethyl ether and dried in vacuum to provide the title compound as a white solid (103 mg, 0.458 mmol, 75%). 1H NMR (500 MHz, CD3OD): δ (ppm) 8.56 (d, J=2.52 Hz, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 4.15 (s, 3H), 3.23-3.38 ppm (m, 4H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][C:18]([F:21])([F:20])[CH2:17][C@H:16]1[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)=O)(C)(C)C>C(Cl)Cl>[Cl:30][C:26]1[CH:25]=[C:24]([NH:23][CH2:22][C@@H:16]2[CH2:17][C:18]([F:21])([F:20])[CH2:19][NH:15]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CNc1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CN[C@H](CNc2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 101.3 %

Procedure:
TFA (1 mL) was added to the solution of (S)-2-[(3-chloro-phenylamino)-methyl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.0004 mol) in DCM (5 mL) at 0° C. and the reaction mixture was stirred at rt for 12 h. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure using a rotary evaporator and washed with ether (3×10 mL). The crude was basified with sodium bicarbonate and the aqueous layer was extracted with DCM (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and distilled using a rotary evaporator to give the desired (3-chloro-phenyl)-((S)-4,4-difluoro-pyrrolidin-2-ylmethyl)-amine (0.1 g) as a sticky solid.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.C(OC([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:40]=2[F:46])=[N:36][C:35]=1[C:47]([NH:23][C:18]1[CH:19]=[N:20][N:21]([CH3:22])[C:17]=1[C@@H:5]1[CH2:6][CH2:7][C@@H:8]([NH2:9])[C@H:2]([F:1])[CH2:3][O:4]1)=[O:48]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(Cl)ccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(Cl)ccc3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 5-((tert-butoxycarbonyl)amino)-2-(5-chloro-2-fluorophenyl)thiazole-4-carboxylic acid (Intermediate 132) gave 291. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.29 (dd, J=6.5, 2.7 Hz, 1H), 7.73 (bs, 1H), 7.51 (s, 2H), 7.48-7.36 (m, 2H), 7.08-6.53 (m, 1H), 4.85 (dd, J=9.9, 4.1 Hz, 1H), 4.51-4.31 (m, 1H), 4.29-3.93 (m, 2H), 3.78 (s, 3H), 2.18-2.07 (m, 1H), 1.93-1.79 (m, 1H), 1.78-1.62 (m, 3H). LCMS (ES+) m/z 483 (M+1).