Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=1>ClCCl>[C:1]([NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ccccc2N)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccccc2NC(=S)NC(=O)c2ccccc2)c1

Procedure:
A mixture of benzoylisothiocyanate (4 g), 2-amino-3'-methanesulphonylbiphenyl (6.1 g) and dichloromethane (30 ml) at ambient temperature for two hours gave N-benzoyl-N'-(3'-methanesulphonyl-2-biphenylyl)thiourea (m.p. 179°-180° C.).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:17][C@@H:18]([NH2:21])[CH2:19][CH3:20].CCN(C(C)C)C(C)C>CS(C)=O>[C@H:18]([NH:21][C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:19][CH3:20])[CH3:17]
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: CC[C@@H](C)N
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](C)Nc1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 73.5 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (0.5 g, 2.1 mmol) in DMSO (10 mL) was added (R)-butan-2-amine (570 mg, 7.79 mmol) and DIEA (850 mg, 6.58 mmol). The resulting solution was stirred for 4 hours at 70° C. and then quenched by the addition of water (50 mL). The solids were collected by filtration to afford (R)-methyl 3-(sec-butylamino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a white solid (425 mg, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[O:10]1[CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11]1>>[OH:10][CH:12]([CH2:13][CH2:14][CH3:15])[CH2:11][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CCCC1CO1
Reactant: O=Cc1cccc(O)c1
Product: CCCC(O)COc1cccc(C=O)c1

Procedure:
Alkylation reaction of 3-hydroxybenzaldehyde with 1,2-epoxypentane gave 3-(2-hydroxypentyloxy)benzaldehyde as a clear oil. Yield (0.6 g, 24%): 1H NMR (400 MHz, CDCl3) δ 9.97 (s, 1H), 7.42-7.49 (m, 2H), 7.40 (s, 1H), 7.21 (d, J=7.2 Hz, 1H), 4.04 (d, J=7.2 Hz, 2H), 3.87-3.93 (m, 1H), 2.28 (d, J=3.6 Hz, 1H), 1.42-1.62 (m, 4H), 0.98 (t, J=6.8 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>CN(C)C=O>[C:13]([O:16][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2)(=[O:15])[CH3:14]
Reactant: BrCc1cccc2cccnc12
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cccc2cccnc12
Yield: 85.5 %

Procedure:
8-Bromomethylquinoline (1.11 g) and sodium acetate (0.82 g) were suspended and dissolved in dimethyl formamide, and heated for 2 hours at 80° to 90° C. After completion of the reaction, dimethyl formamide was distilled off, and the residue was extracted with a mixed solvent of ethyl acetate-toluene (3:1). The solvent was distilled off to give 8-acetoxymethylquinoline (0.86 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]1C(=O)O[C:22](=[O:23])[C:21]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:20]12>>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:23]
Reactant: Cc1cccc(-n2c(=O)oc(=O)c3ccccc32)c1C
Reactant: Oc1n[nH]c2ccccc12
Product: Cc1cccc(Nc2ccccc2C(=O)n2nc(O)c3ccccc32)c1C
Yield: 42.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-(2,3-dimethylphenyl)isatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 42.5% yield; m.p. 182°-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([OH:17])([CH3:16])[CH3:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[S:28][C:27]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(C)(C)O)cc(-c3ccc(Cl)cc3)nc12
Product: CC(C)(O)c1cc(-c2ccc(Cl)cc2)nc2c(C#Cc3ccc(S(N)(=O)=O)s3)cnn12

Procedure:
The title compound was prepared from 2-[5-(4-chloro-phenyl)-3-ethynyl-pyrazolo[1,5-a]pyrimidin-7-yl]-propan-2-ol (example C.13) (78 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (76 mg, 64%). MS (ISP) 473.0 [(M+H)+]; mp 206–208° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][O:19][CH:20]1[CH2:24][CH2:23][N:22]([CH:25]2[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]2)[CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:31][CH:28]1[CH2:27][CH2:26][CH:25]([N:22]2[CH2:23][CH2:24][CH:20]([O:19][CH3:18])[CH2:21]2)[CH2:30][CH2:29]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: COC1CCN(C2CCC(N)CC2)C1
Product: COC1CCN(C2CCC(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)C1
Yield: 44.5 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 4-(3-methoxypyrrolidin-1-yl)cyclohexanamine (297 mg, 1.5 mmol) to afford the desired product (210 mg, 45%) as a yellow solid: ESI MS m/z 472 [C24H30BrN3O2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[S:17])[NH:15][N:14]=[CH:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N:12]2[C:16](=[S:17])[NH:15][N:14]=[CH:13]2)[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-n2cn[nH]c2=S)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-n2cn[nH]c2=S)ccc1OC
Reaction time: 72 h

Procedure:
Treat a solution of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid (6.66 g, 26.5 mmol) and methanol (80 mL) under argon via syringe dropwise with thionyl chloride (2.9 mL, 40 mmol). Stir for three days and remove the methanol in vacuo. Purify the residue by flash chromatography (silica gel, 9.5×12.7 cm) eluting with 40% ethyl acetate in dichloromethane and then with ethyl acetate. Concentrate the desired fractions in vacuo to afford 4.55 g of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]C.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:22]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCBr
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1-c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(OCc3ccccc3)cc2)c1
Yield: 75.7 %

Procedure:
A solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]phenol (1.80 g, 5.07 mmol), 1-bromoundecane (1.58 ml, 7.60 mmol) and potassium carbonate (1.05 g, 7.06 mmol) in DMF (15 ml) was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.90 g (yield: 75.7%)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:11]O)=[N:5][CH:6]=[C:7]([O:9][CH3:10])[N:8]=1.O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][C:4]1[C:3]([O:2][CH3:1])=[N:8][C:7]([O:9][CH3:10])=[CH:6][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cnc(CO)c(OC)n1
Solvent: ClCCl
Product: COc1cnc(CCl)c(OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3,5-dimethoxy-pyrazin-2-yl)-methanol (100 mg, 0.59 mmol) in DCM (5 mL) was added SOCl2 (5 eq) at room temperature. The mixture is stirred at room temperature for an additional one hour. Solvent and volatile materials are removed in vacuo to dryness to give 110 mg of 2-chloromethyl-3,5-dimethoxy-pyrazine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C1CNCCNC1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N1CCCNCC1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
The 1-(4-chlorophenylsulphonyl)homopiperazine was prepared as follows. 4-Chlorophenylsulphonyl chloride (3.74 g) in dichloromethane (100 ml) was added slowly to a solution of homopiperazine (6.73 g) in dichloromethane (100 ml). The reaction was stood at room temperature overnight. The reaction was washed with water, dried (MgSO4) and the solvent removed in vacuo. The residue was triturated with 20% ether in hexane to give 1-(4-chlorophenylsulphonyl)homopiperazine (3.71 g); NMR (DMSOd6): 1.65 (m, 2H), 2.73 (m, 4H), 3.2-3.65 (m 4H), 7.7 (m, 2H), 7.8 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH:30]([CH2:35][CH:36]3[O:38][CH2:37]3)[C:31]([O:33]C)=[O:32])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH:30]([CH2:35][CH:36]([OH:38])[CH2:37][S:9][C:7]3[O:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=4[N:6]=3)[C:31]([OH:33])=[O:32])(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1nc2ccc(Cl)cc2o1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccc(Cl)cc4o3)C(=O)O)cc2)cc1

Procedure:
Example 37 is prepared from 6-chloro-2-benzoxazolethiol and 1d using the procedure described for compound 20.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=O)[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14](=[S:26])[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A solution of (R)-2-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1.31 g, 6 mmol) in dioxane (20 mL) was treated under argon with Lawesson's reagent (1.16 g, 3 mmol). The mixture was stirred at room temperature overnight. The volatiles were evaporated and the resulting white solid purified by flash chromatography (heptane/ethyl acetate gradient) to yield (R)-2-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid (0.74 g, 47%), MS (ISP): 245.4 (M+H)+..
Reaction SMILES: [N+]([CH:4](C1C=CC=CC=1)[C:5](NC1C=CC=CC=1)=[O:6])([O-])=O.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][C:28](=O)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:24]=[CH:25][CH:26]=1.B.O>O1CCCC1>[N+:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][N:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([OH:20])[CH:22]=2)[C:5](=[O:6])[CH3:4])=[CH:31][CH:32]=1)([O-:38])=[O:37]
Reactant: O=C(Nc1ccccc1)C(c1ccccc1)[N+](=O)[O-]
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1cccc(O)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(CCc1ccc([N+](=O)[O-])cc1)c1cccc(O)c1

Procedure:
10 g (0.4 mol) of the nitrophenylacetanilide prepared in 1a) was placed in a flask and borane in tetrahydrofuran (THF) (1 M, 250 ml) was added carefully. The resulting solution was heated under reflux and water (12 ml) in THF (100 ml) was added dropwise over 1 hour. A further 50 ml of water was added and the mixture was heated for 15 mins. The THF was evaporated under reduced pressure and methanol (100 ml) was added to dissolve the oil. Thin layer chromatography (tlc)(silica H, 20% methanol in chloroform) gave a Rf much higher than the starting acetanilide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].O[C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1cccc(O)c1Cl
Product: COC(=O)[C@H](C)Oc1cccc(C)c1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the 2-chloro-3-methylphenol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])[O:10][C:8](=O)[C:7]=12.[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1C(O)=O>CS(C)=O>[I:1][C:2]1[C:7]2[C:8](=[O:10])[N:14]3[CH2:21][CH2:20][CH2:19][C@H:15]3[C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: O=C1Nc2cccc(I)c2C(=O)N2CCC[C@@H]12

Procedure:
14.5 g (0.050 mol) of 6-iodoisatoic acid anhydride and 6.6 g (0.058 mol) of L-proline in 50 ml of dimethyl sulphoxide are warmed to 70° for 30 minutes, the solvent is removed in a high vacuum and the oil obtained is heated at 170° for 15 minutes. The crude product is purified by chromatography on silica gel using methylene chloride and a mixture of methylene chloride and ethyl acetate for the elution. There is obtained (S)-1,2,3,11a-tetrahydro-6-iodo-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione which melts at 212°-215° after recrystallization from methanol.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([SH:20])[C:13]3[CH:14]=[CH:15][N:16]=[CH:17][C:18]=3[CH:19]=2)=[CH:6][CH:5]=1.[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29]Br)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:21]([O:25][C:26](=[O:31])[NH:27][CH2:28][CH2:29][S:20][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][N:16]=[CH:17]2)([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc(-c2cc(S)c3ccncc3c2)cc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: COc1ccc(-c2cc(SCCNC(=O)OC(C)(C)C)c3ccncc3c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
To 7-(4-methoxy-phenyl)-isoquinoline-5-thiol sodium salt (0.29 g, 1 mmol) in acetone (10 mL), add (2-bromo-ethyl)-carbamic acid tert-butyl ester (0.22 g, 1 mmol) and potassium carbonate (0.14 g, 1 mmol). Stir the mixture at room temperature for 4 hr then load onto a silica gel column, and elute with 65% ethyl acetate in hexane to afford the title compound (0.35 g, 86%). Mass spectrum (LCMS) m/z=355.2 (M+H+).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([C:20]([O:22]C)=[O:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[ClH:24]>O1CCOCC1>[ClH:24].[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:3])=[O:2]
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(=O)O)cnc32)cc1
Temperature: 65 °C
Reaction time: 72 h
Yield: 72.4 %

Procedure:
To a solution of methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (2.5 g, 7.5 mmol) in 1,4-dioxane (50 mL) was added aqueous 6 N HCl (50.0 mL, 1650 mmol) and the reaction mixture was stirred at about 65° C. for about 5 h and at room temperature for about 72 h. The mixture was re-heated to about 60° C. for about 3 h, and stirred at room temperature for about 48 h. The mixture was re-heated to about 65° C. for about 2 h and then cooled to room temperature. An insoluble bright yellow residue was removed by filtration and the organic solvent was removed under reduced pressure to give a precipitate that was collected and dried to give 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid hydrochloride (1.92 g, 72%) as a tan solid: LC/MS (Table 2, Method a) Rt=1.48 min; MS m/z: 352 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:22]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH3:22])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CNc1ncnc2ccc(-c3cccc(F)c3)nc12

Procedure:
Following the same reaction and purification procedure, the amine 1 (150 mg, 0.62 mmol) was treated with sodium hydride 60% dispersion in mineral oil (37 mg, 0.94 mmol) and iodomethane (0.04 mL, 0.62 mmol) to provide 6-(3-fluorophenyl)-N-methylpyrido[3,2-d]pyrimidin-4-amine 26. LC/MS (ESI+): m/z 255 (M+H). 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.38-8.19 (m, 1H), 8.19-8.03 (m, 3H), 7.96 (d, J=8.5 Hz, 1H), 7.58 (dd, J=14.3, 7.8 Hz, 1H), 7.32 (dd, J=10.1, 8.0 Hz, 1H), 3.49 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>C(OCC)(=O)C.CO>[CH3:18][N:19]([CH3:21])[CH:20]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)C=CC(=O)c1cccc(N(C)S(C)(=O)=O)c1
Yield: 88.6 %

Procedure:
1.58 g (6.96 mmol) of N-(3-acetyl-phenyl)-N-methyl-methanesulfonamide were dissolved in 15 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.12 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methyl methanesulfonamide as a yellowish-white solid were obtained (yield 88.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[NH:13][C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:28]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[N:13]([CH3:28])[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2c3ncccc3NC(=O)c3cccnc32)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2c3ncccc3C(=O)N(C)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
10.0 g (0.030 mol) of 5,11-dihydro-11-[(4-methoxyphenyl)methyl]-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one was added to a flask containing 2.16 g of a 50% dispersion of sodium hydride in mineral oil and 100 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 30 min. and then heated to 50° C. for 30 min. After cooling, 8.51 g (0.060 mol) of methyl iodide in 10 ml of dimethylformamide was added dropwise and the mixture was allowed to stir at room temperature overnight. Excess sodium hydride was decomposed by the careful addition of ice. Water was then added, and the product was extracted with ether, dried (anhydrous sodium sulfate), and concentrated to give 10.3 g (99% of theory) of 5,11-dihydro-11-[(4-methoxy-phenyl)-methyl]-5-methyl-6H-dipyrido-[3,2-b:2',3'-e][1,4]diazepin-6-one as a light yellow oil suitable for use in the next reaction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46](Cl)=[N:45][CH:44]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C.O>[C:33]1([NH:39][C:40](=[O:49])[O:41][CH2:42][C:43]2[S:47][C:46]([C:20]3[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32])=[CH:22][CH:21]=3)=[N:45][CH:44]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: O=C(Nc1ccccc1)OCc1cnc(Cl)s1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(COC(=O)Nc3ccccc3)s2)cc1

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with (2-chloro-1,3-thiazol-5-yl)methyl N-phenylcarbamate (136 mg, 0.5 mmol). The crude residue stirred in ethyl acetate/water for 16 hours before being filtered, and the aqueous removed using a Varian Chem Elut Column (CE1010). The resulting solution was concentrated and purified by flash chromatography on silica, eluting with methanol/dichloromethane (0-30%) to give the title compound; Mass Spectrum: M+H+-Boc 489.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:16](O)=O>C=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=CO
Reactant: COC1(c2ccc(F)c(F)c2)CCNC1
Agent: C=O
Product: COC1(c2ccc(F)c(F)c2)CCN(C)C1
Temperature: 85 °C

Procedure:
A mixture of (−)-3-(3,4-difluorophenyl)-3-methoxypyrrolidine (0.013 g, 0.061 mmol) in formic acid (1 ml) and formaldehyde (37% solution in water, 1 ml) was heated at 85° C. for 5 h. The solution was allowed to reach room temperature. The crude mixture was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1). The solvent was evaporated. The crude product analyzed by GCMS. Analysis showed 87% conversion. MS m/z (relative intensity, 70 eV) 227 (M+, 5), 212 (26), 197 (30), 141 (47), 57 (bp).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[N:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Brc1ccc(C2CCCN2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)cn1
Reaction time: 2 h

Procedure:
To a suspension of 5-bromo-2-(pyrrolidin-2-yl)pyridine (2.67 g, 11.8 mmol) in DCM (20 mL) at 0° C. was added DIEA (1.5 eq), followed by CbzCl (1.1 eq). The resulting clear solution was warmed to it and stirred for 2 h. The reaction mixture was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes, Rf=0.35 in 50% EtOAc) to afford the titled compound as a brownish oil (3.63 g).