Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][C:6]1[C:7]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:8]=2[NH:9][C:10](=[O:13])[CH2:11][N:12]=1.C([BH3-])#N.[Na+].O>C(O)(=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][CH:6]1[NH:12][CH2:11][C:10](=[O:13])[NH:9][C:8]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:7]1=2
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Cl)c(Cl)c1)=NCC(=O)N2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)c(Cl)c1)NCC(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-(3,4-dichloro-benzyl)-7,8-dimethoxy-1,3-dihydro-benzo[e][1,4]diazepin-2-one (0.48 g, 1.17 mmol) in glacial acetic acid (1.67 ml) and methanol (9.4 ml) was stirred at 0° C. under nitrogen. Sodium cyanoborohydride (0.148 g, 2.23 mmol) was added portionwise and the reaction mixture was stirred at 0° C. for 30 min, and then at RT for 2 h. Water (17 ml) was added dropwise and the product was extracted with dichloromethane, washed with aqueous 1N ammonia. The organic phase was dried over magnesium sulfate, filtered and the solvent was removed under vacuum. The resulting yellow oil crystallized under HV (0.19 g, 41%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[NH:37]([CH2:41][CH2:42][OH:43])[CH2:38][CH2:39][OH:40].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][OH:43])[C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:34])[F:35])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25]
Reactant: OCCNCCO
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(CCO)CCO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step F (0.50 g, 1.02 mmol) and diethanolamine (0.13 g, 1.24 mmol) in N,N-dimethylformamide (4 mL) was added 1-hydroxybenzotriazole (0.15 g, 1.11 mmol) and 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.22 g, 1.15 mmol) followed by N,N-diisopropylethyl amine (0.27 mL, 1.55 mmol). The reaction mixture was stirred overnight, then diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in chloroform provided the title compound (0.46 g) as a white foam.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][OH:18]>CO>[OH:18][N:17]=[CH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)c2ccccc12
Reactant: NO
Solvent: CO
Product: COC(=O)c1ccc(C=NO)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-formyl-1-naphthalenecarboxylate (2.2 g, 10.3 mmol) in methanol (50 mL) was added a solution of hydroxylamine (1.33 mL, 50% in water). After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure to provide the title compound as a pale yellow solid (2.55 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:6][C:5]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[NH:20][C:19]2=O)=[C:4]([F:30])[CH:3]=1.P(Cl)(Cl)([Cl:33])=O.C(N(CC)CC)C.C1(C)C=CC=CC=1>O>[Cl:33][C:19]1[N:18]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[CH:3][C:4]=2[F:30])[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[N:20]=1
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Yield: 75.4 %

Procedure:
A mixture of 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione(4.5 g, 0.01 mol), phosphorus oxychloride(1.5 g, 0.01 mol), triethylamine(2.0 g, 0.02 mol) and toluene(14 ml) was heated under reflux for 24 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution contained 3.5 g(yield 76%) of the above compound III-1(HPLC analysis). The ethyl acetate solution was concentrated and purified by column chromatography on silica gel(20% ethyl acetate/hexane) to give compound III-1 as a white solid, m.p.128-131° C.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].OO.[Cl:9][C:10]1[CH:11]=[C:12]([C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[C:32]([F:38])[CH:31]=2)[CH:13]=[C:14]([Cl:29])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:18]1=[O:28]>CS(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([NH2:37])=[O:2])=[C:32]([F:38])[CH:31]=2)[CH:13]=[C:14]([Cl:29])[C:15]=1[CH2:16][CH:17]1[CH2:21][CH2:20][N:19]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:18]1=[O:28]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1F
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1F

Procedure:
Add potassium carbonate (83 mg, 0.6 mmol) and hydrogen peroxide (30% in water, 0.5 mL) to a solution of Preparation 13 (3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-3-fluoro-biphenyl-4-carbonitrile) (88 mg, 0.2 mmol) in DMSO (3 mL). Stir the reaction at room temperature for 12 h. Partition the mixture between ethyl acetate (20 mL) and water (20 mL). Separate the organic layer, wash three times with water (15 mL each) then brine (15 mL). After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 1:1 ethyl acetate/hexane to afford the title compound: MS (m/z): 463 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH:11]=[C:12]([CH3:14])[CH3:13])[N:8]=[C:7]([CH3:15])[CH:6]=1)[CH3:2]>C1COCC1.CO.[Pd]>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([CH2:11][CH:12]([CH3:13])[CH3:14])[N:8]=[C:7]([CH3:15])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)nc(C=C(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)nc(CC(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
2-Methyl-6-(2-methyl-propenyl)-isonicotinic acid ethyl ester (9.90 g, 45.2 mmol) is dissolved in THF (100 mL) and methanol (100 mL), Pd/C (800 mg, 10% Pd) is added and the mixture is stirred under 1 atm H2 at rt for 5 h. The catalyst is filtered off and the filtrate is evaporated. The crude product is purified by CC on silica gel eluting with hexane:EA 1:1 to give 2-methyl-6-(2-methyl-propyl)-isonicotinic acid ethyl ester (9.78 g) as a colourless oil; LC-MS: tR=0.71 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:7]=1.CC(C[AlH]CC(C)C)C.Cl>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:6]([CH:7]=1)[CH2:8][NH:12][C:11]([CH3:14])([CH3:13])[CH2:10][OH:9]
Reactant: CC1(C)COC(c2cc(Br)ccc2CCc2ccccc2)=N1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCOCC
Product: CC(C)(CO)NCc1cc(Br)ccc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To 2-(5-bromo-2-(phenethyl)phenyl)-4,4-dimethyl-4,5-dihydrooxazole (20 g) in diethyl ether (70 ml) at 0° C. was added DIBAL (168 ml, 1 Mol solution in CH2Cl2). The mixture was stirred at ambient temperature for 18 hours and cooled to 0° C. Aqueous 2N HCl was added to destroy excess DIBAL, the resulting solid was filtered off and suspended in a mixture of water and ethyl acetate. Triethylamine was added until the white solid was dissolved. The organic layer was separated, dried (MgSO4) and evaporated to give 2-(N-(5-bromo-2-(phenethyl)benzyl)amino)-2-methylpropan-1-ol (14.21 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([NH2:15])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([N:15]3[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]3[CH3:25])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:17]
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CCN(CC)c1ccc(-c2ncc(N)s2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCN(CC)c1ccc(-c2ncc(-n3c(C)nc(C)cc3=O)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
To a solution of 2-(4-(diethylamino)phenyl)thiazol-5-amine (0.45 g, 1.82 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (4.5 mL, 9.0 mmol, 2 M in toluene) dropwise at rt. The reaction mixture was stirred at rt for 1 h, followed by the addition of a solution of methyl 3-acetaminocrotonate ((315 mg, 2 mmol) in anhydrous CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography to give the title compound as a yellow solid (22 mg, 3%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][NH:12][C:11]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CS(O[CH2:24][C:25]#[CH:26])(=O)=O.O>C(C(C)=O)C(C)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][CH2:9][N:10]1[C:14](=[O:15])[CH2:13][N:12]([CH2:26][C:25]#[CH:24])[C:11]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNC(=O)N1COCc1ccccc1
Reactant: C#CCOS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C#CCN1CC(=O)N(COCc2ccccc2)C1=O
Yield: 78.4 %

Procedure:
In 8 ml of methyl isobutyl ketone were dissolved 500 mg (2.27 mmoles) of 3-benzyloxymethyl-imidazolidine-2,4-dione and 37 mg (0.115 mmoles) of tetrabutylammonium bromide followed by addition of 114 mg (2.85 mmoles) of sodium hydroxide at room temperature with stirring. Thereafter, 610 mg (4.55 mmoles) of propargyl methanesulfonate was added dropwise at room temperature with stirring and the mixture was further stirred at room temperature for 7 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate =3:1) to give 461 mg (1.78 mmoles) of 3-benzyloxymethyl-l-propargylimidazolidine-2,4-dione.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH2:15][O:16][CH3:17])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])#[N:3].[CH2:18]([OH:20])[CH3:19]>>[CH2:18]([O:20][C:2]([C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([CH2:15][O:16][CH3:17])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[NH:3])[CH3:19]
Reactant: CCO
Reactant: CCOC(=O)c1cc(C#N)cc(COC)c1
Agent: Cl
Product: CCOC(=N)c1cc(COC)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
Hydrogen chloride gas was passed through a solution of ethyl 3-cyano-5-methoxymethyl-benzoate (300 mg, 1.368 mmol) in anhydrous ethanol (15 mL) at 0° C. After 3 h, hydrogen chloride gas was stopped and the reaction vessel was sealed with a septum. After stirring at room temperature overnight, the reaction vessel was cooled to 0° C. and the septum was removed. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford ethyl 3-ethoxycarbonimidoyl-5-methoxymethyl-benzoate (200 mg, 49%).
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]([C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[CH2:6][O:7]C)=[O:3].COC(=O)C(CO)NC(=O)C.C(N)C1C=CC=CC=1>>[CH2:12]([NH:11][C:9](=[O:10])[CH:5]([CH2:6][OH:7])[NH:4][C:2](=[O:3])[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Agent: COC(=O)C(CO)NC(C)=O
Solvent: NCc1ccccc1
Product: CC(=O)NC(CO)C(=O)NCc1ccccc1
Yield: 84 %

Procedure:
The U.S. Pat. No. 8,796,488 describes a process for Lacosamide (Scheme-6) using a similar reaction, where the resumes N-acetyl-D,L-serine methyl ester is heated at 65° C. with 5 equivalents of benzylamine to obtain N-acetyl-D,L-serine benzylamide in 84% yield. At such a temperature, significant racemization should take place. The chiral purity of the product was of no consequence because the authors used racemic starting material. The authors achieved the required chiral purity through resolution using 2-(S)-chloro mandelic acid, an expensive resolving agent. Furthermore, the process is complicated by the fact that the acetyl group is removed to free the amino group to facilitate resolution with a chiral acid. The required acetyl group is again introduced at the final step.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:39][C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)O)c2)C1=O
Reactant: Nc1cnccn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3cnccn3)c2)C1=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 22 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.08 0 mL, 0.60 mmol) was added to a solution of 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 30) (202 mg, 0.49 mmol) in DCM (5 mL) and stirred at ambient temperature for 50 minutes. 2-Amino-pyrazine (CAS no. 5049-61-6) (94 mg, 0.98 mmol) and pyridine (0.80 mL, 0.98 mmol) were added and the reaction stirred for 16 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate (40 mL), washed with saturated sodium bicarbonate (20 mL), water (10 mL), and brine (10 mL), dried (MgSO4) and evaporated under reduced pressure to give the crude product. The residue was purified by chromatography on silica, eluting with a gradient of 0-4% methanol in DCM to give product (53 mg, 22%). 1H NMR δ300 MHz, CDCl3) 2.13-2.27 (m, 1H), 2.35 (quintet, 2H), 2.52-2.67 (m, 1H), 2.93 (s, 3H), 3.34-3.59 (m, 2H), 4.24 (t, 2H), 4.70 (t, 2H), 4.94 (t, 1H), 6.98 (s, 1H), 7.23 (s, 1H), 7.39 (d, 1H), 7.48 (s, 1H), 8.12 (d, 1H), 8.27 (q, 1H), 8.33 (d, 1H), 8.39 (d, 1H), 8.66 (s, 1H), 9.66 (s, 1H); m/z 489 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O=[CH:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]1.CC(O)=O.[Na]>ClCCCl.O>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][CH2:23][C@H:24]3[CH2:25][CH2:26][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:28][CH2:29]3)[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:12][CH2:13][CH2:14]2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: [Na]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-tert-butyl-4-cyclobutyl-6-(piperazin-1-yl)pyrimidine (7.16 g, 26.1 mmol) and tert-butyl trans-4-(2-oxoethyl)cyclohexylcarbamate (6 g, 24.86 mmol) in DCE (100 ml) was stirred at room temperature for 10 min. AcOH and sodium triacetoxyhydroborate (7.90 g, 37.3 mmol) were added. After 4 h, water was added. The aqueous layer was extracted with methylene chloride (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a yellow oil of (11.2 g, 21.29 mmol, 86% yield) which was used next step without purification.
Reaction SMILES: [CH3:1][C@H:2]([CH2:11][NH2:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].C(N([C@H](C1C=CC=CC=1)[C@@H](C)C(OC)=O)[C@H](C)C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][C@@H:2]([CH2:11][NH2:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4]
Reactant: C[C@H](CN)[C@@H](N)c1ccccc1
Agent: COC(=O)[C@H](C)[C@@H](c1ccccc1)N(Cc1ccccc1)[C@H](C)c1ccccc1
Product: C[C@@H](CN)[C@H](N)c1ccccc1

Procedure:
The title compound was prepared as described in the example for the synthesis of the enantiomer, (1R,2R)-2-methyl-1-phenyl-1,3-propanediamine, from methyl (2R,3S,αR)-3-(N-benzyl-N-α-methylbenzylamino)-2-methyl-3-phenylpropionate (Davies et al., J. Chem. Soc. Chem. Commun. 1153-1155, 1993). The title compound was obtained as a crystallizing oil, MS (m/z): 165.3 (M+H)+; C10H16N2 requir. 164.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[H-].[Na+].Cl[C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:20][O:21][C:25]1[CH:26]=[C:27]2[N:34]([CH3:35])[CH2:33][CH2:32][N:28]2[C:29](=[O:31])[N:30]=1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Reactant: OCc1cc(F)c(Oc2cncc(C(F)(F)F)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3cncc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using (3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (250 mg, 0.819 mmol) in DMF (5 mL), sodium hydride (59.0 mg, 2.46 mmol) and 7-chloro-1-methyl-2,3-dihydroi-midazo[1,2-c]pyrimidin-5(1H)-one (152 mg, 0.819 mmol).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:6]=1.[NH2:14][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:16][OH:17]>C(Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:14][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:16][OH:17])[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(-c2csc(Br)n2)cc1
Reactant: CCC[C@@H](N)CO
Solvent: ClCCl
Product: CCC[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 150 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
A mixture of 2-bromo-4-(4-bromophenyl)-1,3-thiazole (2.9 g, 9.09 mmol), prepared in step 2 of Example 1, and (R)-(−)-2-amino-pentanol (2.82 g, 27.2 mmol) was stirred under nitrogen at 150° C. for 18 h. After cooling to room temperature, the residue was taken up in methylene chloride, applied to a Biotage FLASH 40+™ cartridge and the methylene chloride allowed to evaporate. Purification of the residue on the samplet on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of 5% ethyl acetate-hexane to 100% ethyl acetate gave (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}pentan-1-ol (2.56 g, 83%) as a yellow solid, mp 63-65° C.; MS (ESI) m/z 341 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]([OH:28])=O)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:30][NH:31][CH3:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]([N:31]([CH3:32])[CH3:30])=[O:28])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CNC
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C(=O)O)n1
Agent: Cl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1csc(C(=O)N(C)C)n1
Yield: 23.42 %

Procedure:
(S)—N4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-N2,N2-dimethylthiazole-2,4-dicarboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylic acid (0.2 g, 0.428 mmol) and dimethylamine hydrochloride (0.029 g, 0.357 mmol). The product was purified by Flash-chromatography. Yield 23.42%. 1H-NMR (400 MHz; DMSO-d6): δ 1.18 (d, 3H), 3.05 (s, 3H), 3.45 (s, 3H), 4.37 (m, 2H), 4.46 (m, 1H), 6.94 (d, 1H), 7.84 (d, 1H), 7.89 (dd, 1H), 7.95 (d, 1H), 8.04 (d, 1H), 8.30 (d, 1H), 8.43 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](Cl)(Cl)[Cl:10])=[CH:4][N:3]=1.C(O)(=O)C>[Zn].CO>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][Cl:10])=[CH:4][N:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cnc1Cl
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: ClCc1cnc(Cl)c(Cl)c1
Temperature: -5 °C
Reaction time: 4 h

Procedure:
2,3-dichloro-5-trichloromethylpyridine (36.60 g, 0.139 mol) was added to a flask containing acetic acid (53.50 g, 0.892 mol) and methanol (200 mL). The mixture was cooled to −5° C., and zinc dust (20.01 g, 0.308 mol) was added in small portions at 10 minute intervals. The mixture was stirred mechanically for 4 hours, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with brine, followed by saturated aqueous sodium bicarbonate, followed by a second brine wash. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield 21.55 g (79%) of Preparatory Compound P, 2,3-dichloro-5-(chloromethyl)pyridine, as a yellow liquid (about 65% purity). 1H NMR δ 8.31 (d, 1H, J=2.3 Hz), 7.85 (q, 1H, J=0.4 Hz and J=2.2 Hz), 4.56 (s, 2H). MS (ESI) m/z 199 ([M+4]+, 8), 197 ([M+2]+, 27), 195 ([M]+, 28), 164 (11), 162 (66), 160 (100), 124 (19)