Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[S:15](=[O:18])(=[O:17])[NH2:16].[CH3:19][N:20]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[CH2:33][C:21]1=2>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:30]2[CH:29]=[CH:28][C:27]3[C:22]4[CH2:23][CH2:24][C:25](=[O:26])[N:20]([CH3:19])[C:21]=4[CH2:33][C:32]=3[CH:31]=2)=[O:11])=[CH:8][C:7]=1[S:15]([NH2:16])(=[O:18])=[O:17]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: CN1C(=O)CCC2=C1Cc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1C(=O)CCC2=C1Cc1cc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Under nitrogen, aluminum chloride (2.0 g, 15.06 mmol) is slurried in dichloromethane (100 mL) then 4-chloro-3-sulfamoyl-benzoyl chloride (1.28 g, 5.02 mmol) is added and allowed to stir at ambient temperature for 30 minutes. To this mixture 1-methyl-1,3,4,9-tetrahydro-indeno[2,1-b]pyridin-2-one (1.0 g, 5.02 mmol) is added in 13 mL dichloromethane. The reaction is allowed to stir at ambient temperature for 1 hour. The reaction mixture is poured over ice-water (300 mL) and extracted with dichloromethane, organic separated and concentrated to give crude title compound. Recrystallization from warm methanol afforded the title compound as a yellow powder (1.11 g, 53% yield). 1H NMR (MeOD) δ 2.77-2.83 (m, 4H), 3.28 (s, 3H), 3.59 (s, 2H), 5.17 (s, 2H), 7.19 (d, 1H, J=7.83 Hz), 7.68-7.73 (m, 2H), 7.86 (s, 1H), 7.94 (dd, 1H, J=2.27, 8.33 Hz), 8.46 (d, 1H, J=2.02 Hz), MS (m/z): 417 (M+1). M.P. 259-260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([CH:19]=2)[CH:17]=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21].[NH:22]1[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]1.CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([CH:19]=2)[CH2:17][N:22]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21]
Reactant: CCC(Nc1ccc(C)c(C=O)c1)c1ccc(Cl)c(C)c1
Reactant: O=C(O)C1CNC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC(Nc1ccc(C)c(CN2CC(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of INT 9 (200 mg, 0.66 mmol) and azetidine-3-carboxylic acid (67 mg, 0.66 mmol) in MeOH (6.5 mL) was added HOAc (0.038 mL, 0.66 mmol) followed by NaCNBH3 (42 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to afford the title compound Example 4.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:6]([C:3]3([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]3)=[O:7])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)C3(C(F)(F)F)CC3)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 1-trifluoromethylcyclopropanecarboxylic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (72% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.83, 6.98, 3.90-3.80, 3.48, 1.66, 1.48, 1.39-1.35, 1.18-1.14, 0.92. MS (ES+) m/z 414.2 (M+1).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[F:21][C:22]([F:29])([F:28])[C:23]1[CH:24]=[N:25][NH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:21][C:22]([F:29])([F:28])[C:23]1[CH:24]=[N:25][N:26]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=3[N:12]=2)[CH:27]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-n3cc(C(F)(F)F)cn3)nc2c1
Temperature: 50 °C
Yield: 91.1 %

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.18 g of 4-(trifluoromethyl)pyrazole, 0.55 g of potassium carbonate and 2 ml of DMF was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 2-{3-[4-(trifluoromethyl)pyrazole-1-yl]pyridin-4-yl}-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 62”).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]([F:20])=[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)[CH:8]=1.C([O-])(=[O:24])C.[Na+].O>CN(C=O)C>[Cl:21][C:4]1[CH:5]=[C:6]([F:20])[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:8][C:3]=1[CH2:2][OH:24]
Reactant: Cn1nc(-c2cc(CBr)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cc(CO)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of 7.1 g (0.0175 mole) 3-[5-(bromomethyl)-4-chloro-2-fluorophenyl]-4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 20 mL DMF was added 1.5 g (0.018 mole) sodium acetate. The mixture was stirred for 12 hours at 25° C. The mixture was poured into 100 mL cold water and the solid filtered and dried. The product was recrystallized from ethanol/-water to give 6.0 g (90%) of 2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorobenzenemethanol, acetate (ester), mp 90° C. The acetate was dissolved in 10 mL 1,4-dioxane and 10 mL water and 6.3 mL (0.0158 mole) 10% NaOH solution was added. After 30 minutes the solution was neutralized with concentrated HCl, filtered and the solid dried. The solid was recrystallized from ethanol/water to give 5.4 g (99%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol as a white solid; mp 103° C.
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:18][C:19]([C:21]1([NH2:31])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Br:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:16]([O:18][C:19]([C:21]1([NH:31][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Br:30])[CH:27]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(N)Cc2ccc(Br)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC2CCC2)Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 2-cyclobutoxy-3-methyl-benzoic acid (250 mg, 1.21 mmol), 2-amino-5-bromo-indan-2-carboxylic acid ethyl ester (344 mg, 1.21 mmol), HATU (551 mg, 1.45 mmol) in anhydrous DMF (10 mL) is added DIPEA (240 μL, 1.45 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (50 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-70% EtOAc in heptane) to give a pure product (100) as a colorless oil (520 mg, 91%).
Reaction SMILES: C[C@H](N)C1C=CC=CC=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:15]([C@H:17]1[CH2:25][CH:24]=[CH:23][CH2:22][C@H:18]1[C:19]([OH:21])=O)=O.[ClH:31].Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([NH:39][NH2:40])[CH2:35][CH2:34]1.C(N(CC)CC)C>C(O)CC>[ClH:31].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:15]2[C@@H:17]3[C@@H:18]([CH2:22][CH:23]=[CH:24][CH2:25]3)[C:19](=[O:21])[N:39]([CH:36]3[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]3)[N:40]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OC
Reactant: NNC1CCNCC1
Agent: C[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCCO
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Temperature: 25 °C

Procedure:
A solution of 50 mmol of the salt of (S)-(−)-α-methylbenzylamine and (cis)-2-(3,4-dimethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid (starting compound A8), 55 mmol of piperidin-4-yl-hydrazine dihydrochloride and 100 mmol of triethylamine in 150 ml of 1-propanol is refluxed for 18 h. After cooling to RT, the precipitate is filtered off and dried. M. p. 285-288° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:12]([C:10]1[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)[CH3:13]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC[C@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-chloro-8-[(3S)-3-hydroxypiperidin-1-yl]quinolin-7-yl}ethanone (18 mg, 0.059 mmol) and ammonium acetate (45.5 mg, 0.591 mmol) in methanol (0.33 mL) and acetonitrile (0.34 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (7.42 mg, 0.118 mmol). The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude amine was used directly in the next step. LCMS calculated for C16H21ClN3O (M+H)+: m/z=306.1; Found: 306.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:26]3[C:22]([CH3:21])=[N:23][O:24][C:25]=3[CH3:30])=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2c(C)noc2C)CC1
Reaction time: 2 h
Yield: 106.6 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 3,5-dimethylisoxazole-4-carbonyl chloride (0.022 mL, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hr. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (44 mg, 100%). LCMS calculated for C21H22ClN4O3 (M+H)+: m/z=413.1; Found: 413.1.
Reaction SMILES: [C:1]([C:5]([CH3:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[N:8]1[C:21]2[C:12](=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:11]=[CH:10][CH:9]=1>>[OH:6][C:5]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[C:21]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[N:8]3)[N:19]=1)([CH3:7])[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: CC(=O)C(C)(C)C
Product: CC(C)(C)C(C)(O)c1ccc2ccc3cccnc3c2n1

Procedure:
The process of claim 1 wherein methyl t-butyl ketone is coupled with 1,10-phenanthroline to provide 2-[(1-hydroxy-1,2,2-trimethylpropyl)]-1,10-phenanthroline.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[H-].[Na+].I[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][N:15]([S:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[CH3:28])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC#CCOc1ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Yield: 96.2 %

Procedure:
To a solution of tert-butyl 3-({[4-(2-butynyloxy)phenyl]-sulfonyl}amino)propanoate (1.0 g, 2.83 mmol) in dimethylformamide (5 mL) at 0° C. was added sodium hydride (3.39 mmol) followed by iodomethane (211 uL, 3.39 mmol). After 72 hours the reaction mixture was diluted with ethyl acetate and washed with water and brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave tert-butyl-3-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]propanoate (1.0 g) as a colorless oil. Electrospray Mass Spec 368.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](O)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1.[NH:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:24]3[C:22](=[O:23])[NH:21][C:19](=[O:20])[NH:18][CH:25]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2O
Reactant: O=c1cc[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1c[nH]c(=O)[nH]c1=O

Procedure:
The product from step (iii) (1 g) and uracil (3 g) were heated at 100° C. in acetic acid (200 ml) for 16 h. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic phase was collected, dried (MgSO4), and evaporated under reduced pressure to leave a beige solid. The solid was triturated with isohexane/ethyl acetate mixtures and filtered to leave a cream solid. Yield. 1.35 g Used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([O:9][CH2:10][C:11]2([CH2:14]Br)[CH2:13][CH2:12]2)=[O:8])=[CH:5][CH:4]=1.[C-:18]#[N:19].[K+].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([O:9][CH2:10][C:11]2([CH2:14][C:18]#[N:19])[CH2:13][CH2:12]2)=[O:8])=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(C(=O)OCC2(CBr)CC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)OCC2(CC#N)CC2)cc1
Temperature: 35 °C
Reaction time: 48 h
Yield: 17.8 %

Procedure:
261 mg of compound 10a was dissolved in 5 ml ethanol. A solution of 98 mg potassium cyanide in 5 ml water was added and the mixture was stirred at 35° C. for two days. 10 ml of a saturated aqueous sodium bicarbonate was added. The mixture was extracted twice with ethyl acetate. The combined extracts were dried with sodium sulfate and evaporated to give a yellow liquid. Purification with column chromatography (heptane/ethyl acetate 3/1) gave the title compound (38 mg) confirmed by NMR and LC/MS.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11](S(C)=O)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20].O[C@@H]1CC[C@H](NC2C(C#N)=CN=C(S(C)(=O)=O)N=2)CC1(C)C.Cl.[CH3:45][C:46]1[N:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[CH2:57][NH2:58])[N:49]=[N:48][N:47]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([NH:58][CH2:57][C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=3[N:50]3[C:46]([CH3:45])=[N:47][N:48]=[N:49]3)[N:10]=2)[CH2:4][C:3]1([CH3:21])[CH3:20]
Reactant: CS(=O)c1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Reactant: Cc1nnnn1-c1ccccc1CN
Agent: CC1(C)C[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)CC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nnnn1-c1ccccc1CNc1ncc(C#N)c(N[C@H]2CC[C@@H](O)C(C)(C)C2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a mixture of 4-(((1S,4R)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfinyl)pyrimidine-5-carbonitrile and 4-(((1S,4R)-4-hydroxy-3,3-dimethylcyclohexyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (1.0 equiv) in dioxane (0.4M) was added (2-(5-methyl-1H-tetrazol-1-yl)phenyl)methanamine hydrochloride (1.0 equiv.) and DIEA (2.0 equiv.). The mixture was stirred at 120° C. in microwave for 2 h. After completion of the reaction and standard work-up, the desired product was obtained (37% yield). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 8.12 (s, 1H), 7.82-7.78 (m, 1H), 7.63-7.61 (m, 1H), 7.58-7.51 (m, 3H), 7.02-6.92 (m, 1H), 4.32-4.17 (m, 3H), 4.01-3.99 (m, 1H), 3.21-3.14 (m, 1H), 2.41-2.36 (m, 3H), 1.65-1.47 (m, 1H), 1.36 (br, 1H), 1.23-1.17 (m, 2H), 0.81 (s, 3H), 0.73 (s, 3H); MS (ESI) m/z 434.2 [M+H]+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][CH2:10][C:11]2([NH2:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.C(N(CC)CC)C>C(O)CCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:10][C:11]2([NH2:17])[CH2:16][CH2:15][N:14]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:13][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC1(COCc2ccc(Cl)cc2)CCNCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: NC1(COCc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 17 h
Yield: 78.6 %

Procedure:
A degassed mixture of 4-(4-chloro-benzyloxymethyl)-piperidin-4-ylamine dihydrochloride (9.2 mg, 0.028 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.9 mg, 0.035 mmol), triethylamine (36 uL, 0.2 mmol) and n-butanol (0.35 mL) was stirred at 100° C. for 17 h. The solvents were removed by evaporation. The crude mixture was purified on an SCX-II acid resin, eluting with methanol then 2M ammonia/methanol, and then by preparative TLC eluting with 10% methanol in dichloromethane, to give 4-(4-chloro-benzyloxymethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine (8.2 mg, 0.022 mmol, 78%). LC-MS (LCT2) m/z 372 [M+H+], Rt 3.19 min.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1>>[C:9]([NH:8][C:6]1[N:7]=[C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:3]=[CH:4][CH:5]=1)(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)C(=O)Nc1cccc(Br)n1
Product: CC(C)C(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Prepared by Procedure W and Scheme AF using N-(6-bromo-2-pyridinyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 245.8 (M - 100)+.
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH2:18])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH:18][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
The title material from Example 17 step 6 (300 mg, 0.000767 mol) was dissolved in pyridine (5 mL), and to this solution was added methane sulfonyl chloride (88 mg, 0.000767 mol). The resulting solution was stirred at room temperature for 18 hours. The reaction was then concentrated in vacuo, and the resulting solids were triturated with water and the product was isolated by vacuum filtration. 88 mg. (MW=469.48, 25% yield). LC/MS m/z=470.3 (m+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.CC(N(C)C)=O.[C:21]1([NH:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:30][CH2:29][CH2:28][NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: NCCNc1ccccc1
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as described in Method 22; 932 mg, 4.0 mmol) and DMA (0.7 mL, 4.0 mmol) in ACN (40 mL), neat N1-phenyl-ethane-1,2-diamine (0.523 mL, 4.0 mmol) was slowly added. The reaction mixture was stirred at 70-80° C. under nitrogen. After 20 hours, the reaction mixture was cooled down, and the solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (120 mL) and 0.1 M NaHCO3 (50 mL). The organic layer was washed with additional 0.1 M NaHCO3 (2×50 mL), brine (50 mL), dried, filtered and concentrated to give N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine, as an off-white solid (1.29 g, 96%). LC/MS (m/z): 334.0 (MH+), Rt 1.94 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][NH:9][C:8]2=[CH:13][N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[H-].[Na+].[C:21](OC=O)(=[O:23])C>CN(C)C=O>[CH:21]([N:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)[C:8]1=[CH:13][N+:14]([O-:16])=[O:15])=[O:23]
Reactant: CC(=O)OC=O
Reactant: O=[N+]([O-])C=C1NCCCN1Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CN1CCCN(Cc2ccc(Cl)cc2)C1=C[N+](=O)[O-]
Reaction time: 8 h

Procedure:
1-(4-Chlorobenzyl)-2-nitromethylene-hexahydropyrimidine (3 g) was added to a stirred suspension of sodium hydride (0.54 g) in dry dimethylformamide (150 ml) at room temperature under nitrogen and the stirring was continued overnight. Formic acetic anhydride (100% excess) was then added dropwise to the stirred suspension at 0°. The reaction mixture was then stirred for 1 hour. It was then poured onto water and extracted with dichloromethane (2×200 ml). The combined organic layers were dried (sodium sulphate) and the solvent removed in vacuo, to leave a solid. The solid was triturated with chloroform (5 ml) and was then filtered off, washed with chloroform (5 ml) and dried to afford the title compound (1.2 g), m.pt. 131°-133° C.