Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]([C:18]#[N:19])=[CH:10][C:9]=2[CH:20]=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]([C:18]#[N:19])=[CH:10][C:9]=2[CH:20]([OH:21])[CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(C=O)c(-c2cccc(F)c2)c2ncccc12
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(C#N)c2cccnc2c1-c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3-fluorophenyl)-7-formylquinoline-5-carbonitrile (20 mg, 0.07 mmol) in tetrahydrofuran (1 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (0.12 mL, 0.17 mmol) at −78° C. The reaction was stirred at −78° C. for 30 minutes, quenched with water at −78° C. The mixture was neutralized with 1 N HCl, and then extracted with ethyl acetate. The combined orgagnic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step (20 mg, 90%). LCMS calculated for C18H14FN2O (M+H)+: m/z=293.1; Found: 293.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([I:12])[CH:4]=1.C(O)(=O)C>CO.O.[Fe]>[I:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[NH2:9]
Reactant: COc1ccc([N+](=O)[O-])c(I)c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccc(N)c(I)c1
Temperature: 70 °C
Yield: 89.2 %

Procedure:
To a suspension of 3-iodo-4-nitrophenyl methyl ether (5.0 g, 0.018 mol) in methanol (50 mL), water (5 mL), and acetic acid (10 mL) was added iron (3.00 g, 0.0538 mol) powder in small quantities. When the addition was completed, the reaction mixture was heated at 70° C. overnight. After filtration, the cake was rinsed with EtOAc. The filtrate was concentrated and the residue was diluted with NaHCO3 (aq) and EtOAc. After layer separation, the organic layer was dried, filtered and concentrated to give the desired product (4.0 g, 90%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29](O)=[O:30])[CH:22]=2)=[N:8][CH:7]=1)=[O:5])C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[C:9]([C:20](=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:30])[CH:22]=1)=[N:8][CH:7]=[C:6]2[C:4]([OH:3])=[O:5]
Reactant: CCOC(=O)c1cnc(C(=O)c2cccc(OCC(=O)O)c2)c2cc(OC)c(OC)cc12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(C(=O)O)cnc(C(=O)c3cccc(OCC(=O)N4CCOCC4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
To a solution of 1-(3-carboxymethoxybenzoyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid ethyl ester (93.3 mg, 0.20 mmol) in 8 ml of methylene chloride was added 10 equivalent of morpholine, 1.2 equivalent of HBTU and 4 equivalent of triethylamine. The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was extracted with ethyl acetate and water. The organic phase was dried and solvents were evaporated. The residue was dissolved in 4 ml of methanol and aqueous lithium hydroxide was added (0.5N, 1 ml). The mixture was stirred overnight until all starting material disappeared. The reaction was loaded on a preparative HPLC for purification to give 6,7-Dimethoxy-1-[3-(2-morpholin-4-yl-2-oxo-ethoxy)-benzoyl]-isoquinoline-4-carboxylic acid as a fluffy solid (20 mg, 21%). ES-MS calcd for C25H24N2O8 (m/e) 480.5, obsd 481.3 (M+H).
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([N:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:33]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:32])[N:14]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: Cc1ccc(C=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 256A (0.065 g, 0.142 mmol) in tetrahydrofuran (3.0 mL) and methanol (0.012 mL, 0.284 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.111 mL, 0.222 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (8.0 mL), and the resulting precipitate was collected by filtration and dried. The crude product was triturated with dichloromethane/diethyl ether and filtered to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.32 (s, 3 H) 3.87 (s, 2 H) 6.03 (s, 1 H) 7.10 (m, 1 H) 7.21 (d, J=7.72 Hz, 2 H) 7.30 (t, J=7.17 Hz, 2 H) 7.42 (d, J=7.72 Hz, 2 H) 7.56 (t, J=8.64 Hz, 2 H) 7.70 (t, J=9.38 Hz, 2 H) 8.10 (d, J=7.72 Hz, 1 H) 16.28 (m, 1 H). MS (ESI−) m/z 459 (M−H)−.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:14]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSC>O1CCCC1>[C:1]([SiH2:5][O:6][C:7]([CH3:25])([CH3:24])[CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:14]=2)[CH:9]1[OH:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Cc1ccc2c(c1)C(=O)C(C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc2c(c1)C(O)C(C(C)(C)O[SiH2]C(C)(C)C)CC2
Temperature: -12.5 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a −30° C. cooled solution of 2-(tert-Butyl-dimethyl-silanyloxymethyl)-7-(2,2-dimethyl-propyl)-3,4-dihydro-2H-naphthalen-1-one (2.20 g, 6.09 mmol) in tetrahydrofuran (20 mL) was added (S)-2-methyl-Cbs-oxazaborolidine (1 M in toluene, 0.61 mL, 0.61 mmol) and a solution of borane-methyl sulfide complex (2 M in tetrahydrofuran, 2.15 mL, 4.3 mmol) in tetrahydrofuran (5 mL). The reaction mixture was heated at −20 to −5° C. for 5 h. The reaction mixture was quenched with methanol (8.3 mL) at −5° C. and then allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure. Flash column chromatography (silica gel, 0-5% ethyl acetate/hexanes) recovered 790 mg of ketone and provided chiral 2-(tert-Butyl-dimethyl-silanyloxymethyl)-7-(2,2-dimethyl-propyl)-1,2,3,4-tetrahydro-naphthalen-1-ol (980 mg, 70%): 1H NMR (300 MHz, CDCl3) δ 7.14 (s, 1H), 7.03-6.96 (m, 2H), 4.84 (d, J=2.5 Hz, 1H), 3.92-3.82 (m, 2H), 3.04 (d, J=3.7 Hz, 1H), 2.92-2.67 (m, 2H), 2.46 (s, 2H), 2.04-1.86 (m, 2H), 1.75-1.63 (m, 1H), 0.91 (s, 9H), 0.90 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1>C(O)CCC>[N:1]1([C:17]2[C:18]3[C:25]([C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: N#Cc1cccc(-c2c[nH]c3ncnc(N4CCOCC4)c23)c1

Procedure:
Morpholine (871 mg, 10 mmol) and N,N-diisopropylethylamine (2.6 g, 20 mmol) were added to a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (2.5 g, 9.8 mmol) in n-butanol (100 mL), and the reaction mixture was heated at reflux for 3 hours. Solvents were removed in vacuo and the residue was purified using chromatography on silica gel (Eluent: 1:1 ethyl acetate/petroleum ether). Subsequent recrystallization from ethyl acetate and tert-butyl methyl ether afforded the product as a white solid. Yield: 770 mg, 2.52 mmol, 26%. LCMS m/z 306.0 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br s, 1H), 8.41 (s, 1H), 7.99-8.02 (m, 1H), 7.89 (br d, J=8 Hz, 1H), 7.76 (br d, J=7.5 Hz, 1H), 7.71 (s, 1H), 7.68 (dd, J=7.8, 7.8 Hz, 1H), 3.44-3.50 (m, 4H), 3.11-3.17 (m, 4H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCCC1>C(O)C>[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 69.8 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f (490 mg, 1.53 mmol), 5-fluoro-1,3-dihydro-indol-2-one (219 mg, 1.45 mmol) and piperidine (100 μL, 1.0 mmol) were dissolved in 5 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction mixture was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound (S,Z)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 5 (460 mg, 69.9%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25](=[O:27])(=[O:26])[NH2:24])=[CH:29][CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(N)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 4-(aminosulfonyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 7): tR=1.24 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1N)[CH2:8]2.[CH3:12][CH:13]1[S:17](=[O:19])(=[O:18])[O:16][CH2:15][CH2:14]1.C(#[N:22])C>>[C:1]12([NH:22][CH2:15][CH2:14][CH:13]([S:17]([OH:16])(=[O:19])=[O:18])[CH3:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC1CCOS1(=O)=O
Reactant: CC#N
Reactant: NC1C2CC3CC(C2)CC1C3
Product: CC(CCNC12CC3CC(CC(C3)C1)C2)S(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 2-adamantanamine (1.99 g, 13.1 mmol) in acetonitrile (15 mL) was added 2,4-butane sultone (1.87 g, 13.8 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetonitrile (3×25 mL) and dried in vacuo. 1H NMR (DMSO, 500 MHz) δ ppm 8.53 (s (broad), 1H), 3.33 (m, 2H), 2.61 (m, 1H), 2.10 (s, 3H), 1.93 (m, 1H), 1.77 (m, 7H), 1.61 (m, 6H), 1.12 (d, 1H, J=6.8 Hz). 13C (DMSO, 125 MHz) δ ppm 56.20, 53.34, 35.85, 29.75, 29.04, 17.206. ES-MS 288 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C([O-])([O-])=O.[K+].[K+].O.Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1>[CH2:19]([O:18][C:16]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146 %

Procedure:
To a magnetically stirred solution of piperazin-2-one (2.0 g, 20.0 mmol) in THF (10 mL) at room temperature under Ar atmosphere, K2CO3 (8.25 g, 120 mmol), water (10 mL), and benzyl chloroformate (3.14 mL, 22.0 mmol) were added. The reaction mixture was stirred for 18 hours at room temperature. Water (50 mL) was added, and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic layers were washed with water, dried with MgSO4, and concentrated in vacuo to the give the title compound (6.84 g, 100%). 1H NMR (400 MHz, CDCl3) δ 3.37 (bs, 2H), 3.68 (t, J=4.7 Hz, 2H), 4.13 (s, 2H), 5.14 (s, 2H), 7.34 (m, 5H).
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OC=C)(=[O:12])[CH3:11].C(OCCCCCCCC)=C>C1(C)C=CC=CC=1>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH3:11]
Reactant: CCCCCCCCO
Reactant: C=COC(C)=O
Agent: C=COCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(C)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and 4MgCO3—Mg(OH)2-5H2O (0.6 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and vinyl acetate (2 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 2 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl vinyl ether and octyl acetate were produced in yields of 18% and 3%, respectively, with a conversion from 1-octanol of 44%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([C:14]#[N:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].C([O-])([O-])=O.[K+].[K+]>CCO>[CH2:1]([O:8][C:9](=[O:16])[NH:10][C:11]1([C:14](=[NH:15])[NH:18][OH:19])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#CC1(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Yield: 15.8 %

Procedure:
To a solution of (1-cyano-cyclopropyl)-carbamic acid benzyl ester (3.7 g, 17.11 mmol) in EtOH (40 mL) was added hydroxylamine hydrochloride (3.6 g, 51 mmol) and K2CO3 (9.5 g, 68 mmol). The reaction mixture was heated at reflux for 24 h. The resulting white suspension was cooled to RT and concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc (3×100 mL). The combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered, concentrated and purified by reverse phase HPLC to give [1-(N-hydroxycarbamimidoyl)-cyclopropyl]-carbamic acid benzyl ester (0.68 g, 2.7 mmol) as a white solid.
Reaction SMILES: BrBr.[Br:3][C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11].S(=O)(=O)(O)[OH:13]>>[Br:3][C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:11]=[O:13]
Reactant: Cc1cccc(Br)c1Br
Reactant: O=S(=O)(O)O
Agent: BrBr
Product: O=Cc1cccc(Br)c1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Bromine (168 g., 1.05 mole) is added over about one hour, with vigorous stirring, to 117.5 g. (0.47 mole) of 2,3-dibromotoluene at 190° C. After the addition is complete, the mixture is cooled to 100° C., then 120 cc. of concentrated sulfuric acid is added and the mixture is stirred for one hour at 100° C. Temperature is raised to 140° C. for five minutes, then the mixture is cooled and the reaction is quenched in ice water. The solid is extracted into ether, and the ether extract is washed with water, then dilute aqueous sodium bicarbonate until the acid is completely removed, and filtered. Removing the ether by evaporation gives 2,3-dibromobenzaldehyde as the residue.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[CH3:6][N:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.[N+:14]([CH3:17])([O-])=O>C(O)C.C(O)(=O)C>[C:2]([O:13][C:10]1([CH2:17][NH2:14])[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:1])[CH3:3]
Reactant: CC[O-]
Reactant: C[N+](=O)[O-]
Reactant: CN1CCC(=O)CC1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)OC1(CN)CCN(C)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of sodium ethoxide prepared by dissolving 23 g (1 mole) of sodium in 1500 ml of ethanol was added dropwise a mixture of 113 g (1 mole) of 1-methyl-4-piperidinone and 75 g (1.3 mole) of nitromethane at a rate so as to maintain a temperature (preheated) of 50° C. The solution was stirred for 4 hr and 150 g of acetic acid was added dropwise. The mixture was filtered and the filtrate was concentrated. The residue was crystallized from ethyl acetate. The resulting solid was dissolved in 1 liter of ethanol and treated with 2 teaspoonsful of Raney nickel catalyst. The mixture was hydrogenated for 3 hr at ambient temperature. The residue was crystallized from acetonitrile. Yield of title compound was 80 g (39%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[F:13][C:14]([F:35])([F:34])[C:15]1[CH:16]=[C:17]([S:21]([CH2:24][CH2:25][S:26][C:27]2[C:32]([NH2:33])=[CH:31][CH:30]=[CH:29][N:28]=2)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>S(Cl)(Cl)=O.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:33][C:32]2[C:27]([S:26][CH2:25][CH2:24][S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:34])([F:35])[F:13])[CH:16]=3)(=[O:23])=[O:22])=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COc1cc(F)ccc1C(=O)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A solution of 510 mg (3.0 mmol) 4-fluoro-2-methoxybenzoic acid in thionyl chloride (3 ml) was stirred for 2 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with dioxane (15 ml). Then a solution of 1.09 g (3.0 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) in dioxane (15 ml) and 1.06 g (10.0 mmol) Na2CO3 were added and the mixture was stirred for 16 h at RT. Then the mixture was concentrated to small volume under vacuum and the residue was taken up with water and extracted with EE. The organic phase was washed with a saturated aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Crystallisation (DCM/hexane) of the residue yielded 895 mg (1.7 mmol, 58%) 4-fluoro-2-methoxy-N-[2-[2-[[3-(trifluoromethyl)-phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]-benzamide. MS: m/z 514.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: C1COCCN1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Temperature: 110 °C
Yield: 58 %

Procedure:
A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid (Example A1(a)) in 8 ml morpholine was heated at 110° C. for 15 h. After evaporation of all volatiles the residue was acidified by addition of 1 N HCl and extracted three times with ethyl acetate. The combined organic extracts were washed sequentially with 1 N HCl and saturated brine, dried over sodium sulphate, and concentrated in vacuo to afford the title compound as a light yellow amorphous solid (58%). MS (m/e): 284.1 ([M−H]−, 100%).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH:4]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CCCCO>[CH:19]1([NH:25][C:3]2[CH:4]=[C:5]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=3)[N:6]=[CH:7][N:8]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1cccc(Nc2cc(Cl)ncn2)c1
Reactant: NC1CCCCC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(Nc2cc(NC3CCCCC3)ncn2)c1
Temperature: 200 °C
Yield: 94 %

Procedure:
60 mg of 6-chloro-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride, 32 mg cyclohexylamine and 69 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was precipitated from n-BuOH. Purification was carried out by filtering and washing with cold n-BuOH. Pure N4-cyclohexyl-N6-(3-nitrophenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[N:32]=[CH:31][N:30]([CH3:33])[C:29]=2[CH:34]=1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:33][N:30]1[C:29]2[CH:34]=[C:25]([NH:24]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=[CH:27][C:28]=2[N:32]=[CH:31]1
Reactant: Cn1cnc2ccc(N)cc21
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1cnc2ccc(N/C(=C3\C(=O)Nc4ccccc43)c3ccccc3)cc21

Procedure:
Prepared from 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-2-indolinone and 2 equivalents of 6-amino-1-methyl-benzimidazole, melting point 163-165° C., in DMF followed by treatment with 1N sodium hydroxide solution in MeOH.
Reaction SMILES: [N:1]1([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7]2)[CH2:3][CH2:2]1.P(Br)(Br)[Br:25]>C(Cl)Cl.O>[Br:25][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:1]2[CH2:6][CH2:5][C:4]3([C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH:8]=[CH:7]3)[CH2:3][CH2:2]2)=[CH:17][CH:18]=1
Reactant: OCc1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClCCl
Product: BrCc1ccc(CN2CCC3(C=Cc4ccccc43)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of [4-(spiro[indene-1,4′-piperidine]-1′-ylmethyl)phenyl]methanol (1.5 g, 4.91 mmol) in DCM (50 mL) is added phosphorus tribromide (0.667 mL, 6.8 mmol). The reaction mixture is stirred for 15 minutes at 0° C. The reaction mixture is diluted with water (100 mL) at 0° C. and extracted with DCM (2×200 mL). The combined extracts are washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as an off white solid (1.1 g, 61%). ESI/MS m/z 369 (M+H)+.