Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([CH2:9][C:10]1[C:11]2[CH2:12][C:13]3[N:18]4[CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=[C:17]4[C:16](=[O:27])[NH:15][C:14]=3[C:28]=2[CH:29]=[CH:30][CH:31]=1)([O:6]CC)=[O:5])C.Br.O>C(O)(=O)C>[O:27]=[C:16]1[NH:15][C:14]2[C:28]3[CH:29]=[CH:30][CH:31]=[C:10]([CH2:9][P:4]([OH:6])([OH:5])=[O:3])[C:11]=3[CH2:12][C:13]=2[N:18]2[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=[C:17]12
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CP(=O)(OCC)OCC)c1C3
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CP(=O)(O)O)c1C3
Yield: 61.6 %

Procedure:
A mixture of 0.6 g of ethyl 9-(diethoxyphosphorylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate, 30 ml of hydrobromic acid at 30% in acetic acid and 10 ml of distilled water is heated at reflux for 2 hours. The reaction mixture is filtered and the solid is washed with 3×20 ml of distilled water, and then with 2×10 ml of acetone and finally dried under vacuum (1 mm Hg, 0.13 kPa) at close to 40° C. 0.3 g of 4-oxo-9-phosphonomethyl-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid is obtained in the form of a beige solid melting above 260° C. [Analysis: C15H12N3O6P, 0.09 HBr, 0.38 HCl, 1.54 H2O, % calculated C: 49.87, H: 3.3, N: 11.63, O: 26.57, P: 8.57, % found C: 49.8, H: 3.4, N: 11.1].
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH:12]([C:17]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[N:19]1([C:17]([CH:12]2[C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]([CH2:3][CH2:2][O:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:16]=3[CH2:15][CH2:14][CH2:13]2)=[O:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C1CCCc2c1c1ccccc1n2CCO)N1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCn1c2c(c3ccccc31)C(C(=O)N1CCCCC1)CCC2
Temperature: 0 °C
Yield: 81.3 %

Procedure:
To a solution of [9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (23) (260 mg, 0.8 mmol) in dichloromethane (15 mL) was added pyridine (633 mg, 8.0 mmol, 0.65 mL). The reaction was cooled to 0° C. and methanesulfonyl chloride (458 mg, 4.0 mmol, 0.31 mL) was added. The reaction was allowed to warm to room temperature overnight. The mixture was washed with 2 N HCl (2×50 mL) and water (2×50 mL), dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 263 mg (82%) of methanesulfonic acid 2-[4-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-carbazol-9-yl]-ethyl ester as a white solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 21.4, 21.8, 24.7, 25.9, 26.9, 27.4, 36.6, 36.8, 41.7, 43.3, 47.0, 67.9, 108.5, 109.5, 118.4, 119.7, 121.3, 126.9, 136.2, 172.7.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:11][O:12][C:13](=[O:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18]([CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[O:19])=[CH:16][CH:15]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1ccc(C(=O)C2C(=O)OC(C)(C)OC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A mixture consisting of Meldrum's acid (2 g, 13.9 mmol), terephthalic acid monomethyl ester (2.5 g, 13.9 mmol), EDC (3.5 g, 18 mmol) and DMAP (2.2 g, 18 mmol) in DCM (50 mL) was stirred at RT overnight. The reaction mixture was diluted with DCM (to 100 mL) then washed with water (2×50 mL). The organic solution was dried over Na2SO4 and concentrated to afford 3.9 g of crude 4-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxane-5-carbonyl)-benzoic acid methyl ester as a yellow solid. The crude was carried on as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[H-].[Na+].[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:19])[CH:17]=3)[CH2:29][CH2:28]1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1-c1ccc2cc(NCC3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (61.7 mg, 0.244 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) at room temperature was added sodium hydride (20.1 mg, 0.502 mmol, 60% dispersion in mineral oil). The reaction mixture was stirred at room temperature for 30 minutes, and then cyclopropylmethyl bromide (24.0 uL, 0.247 mmol) was added and the reaction mixture was heated at 50° C. for 3 hours. The reaction mixture was cooled to room temperature and sodium hydride (66 mg, 60% dispersion in mineral oil) was added, followed by cyclopropylmethyl bromide (30.0 uL). The reaction mixture was then stirred at room temperature overnight. The mixture was then partitioned between ethyl acetate and water, and the organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-50% ethyl acetate in dichloromethane) to yield 11.8 mg (16%) of N-(cyclopropylmethyl)-7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine. LCMS (ESI): RT (min)=4.807, M+H=307.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 7.77 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.40-7.30 (m, 1H), 7.17-7.06 (m, 2H), 6.64 (s, 1H), 6.54 (t, J=5.3 Hz, 1H), 3.16 (t, J=6.2 Hz, 2H), 2.25 (s, 3H), 1.12 (dd, J=12.4, 6.7 Hz, 1H), 0.46 (d, J=6.8 Hz, 2H), 0.26 (d, J=4.3 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[C:4]([CH:13]=O)[CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([F:12])=[C:4]([CH2:13][C:23]2[S:22][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[CH:25][CH:24]=2)[CH:3]=1
Reactant: c1ccc(-c2cccs2)nc1
Reactant: O=Cc1cc(Br)c2ccccc2c1F
Product: Fc1c(Cc2ccc(-c3ccccn3)s2)cc(Br)c2ccccc12

Procedure:
The above 4-bromo-1-fluoro-2-naphthaldehyde and 2-(2-pyridyl)thiophene were treated in a manner similar to Reference Example 120 to give the desired 4-bromo-1fluoro-2-(5-(2-pyridyl)-2-thienylmethyl)naphthalene as colorless powder. APCI-Mass m/Z 398/400 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:28])[CH2:21][C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:28])[CH2:21][C:22]1[N:23]=[C:24]([NH:27][C:12]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)=[O:14])[S:25][CH:26]=1)[CH3:18]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)c1cccn1Cc1ccc(F)cc1
Product: CCOC(=O)Cc1csc(NC(=O)c2cccn2Cc2ccc(F)cc2)n1
Yield: 61.9 %

Procedure:
(2-{[1-(4-Fluorobenzyl)-1H-pyrrole-2-carbonyl]-amino}-thiazol-4-yl) acetic acid ethyl ester (60 mg) was prepared from 1-(4-fluorobenzyl)-pyrrole-2-carboxylic acid (55 mg, 0.25 mmol) and 2-aminothiazol-4-yl acetic acid ethyl ester (47 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.[CH3:16][C:17]([CH3:20])([NH2:19])[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:17]([CH3:20])([CH3:18])[CH3:16])=[O:8])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(C)(C)N
Reactant: Cc1cc(C(=O)O)ccc1Br
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)NC(C)(C)C)ccc1Br

Procedure:
From 4-bromo-3-methylbenzoic acid (400 mg), thionyl chloride (0.4 ml) and 1,1-dimethylethanamine (0.8 ml).
Reaction SMILES: [C:1]([C:9]1[C:10]([Cl:16])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:16][C:10]1[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N+:17]([O-:19])=[O:18])[CH:7]=2)=[CH:14][CH:13]=[C:12]([CH3:15])[N:11]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)c(Cl)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)c(Cl)n1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
3-Benzoyl-2-chloro-6-methylpyridine (3.00 g, 12.9 mmol) dissolved in 40 ml of concentrated sulfuric acid was cooled to 5° C. or lower, 1.0 ml of fuming nitric acid was slowly added dropwise thereto, followed by stirring for 30 minutes. The reaction solution was poured into ice water, neutralized with sodium hydroxide aqueous solution and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the solvent was evaporated under a reduced pressure and the resulting residue was recrystallized from ethyl aretate-diisopropyl ether to give 1.81 g (51%) of 2-chloro-6-methyl-3-(3-nitrobenzoyl)pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:9][C:8]([OH:19])([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[N:17][OH:18])=[CH:12][CH:11]=2)[CH2:7]1)=[O:5])[CH3:2].ClN1C(=O)CCC1=O.C(=O)([O-])O.[K+].[Cl:33][C:34]1[CH:39]=[C:38]([C:40]([C:42]([F:45])([F:44])[F:43])=[CH2:41])[CH:37]=[C:36]([Cl:46])[C:35]=1[Cl:47]>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:9][C:8]([OH:19])([C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH2:41][C:40]([C:38]4[CH:37]=[C:36]([Cl:46])[C:35]([Cl:47])=[C:34]([Cl:33])[CH:39]=4)([C:42]([F:45])([F:44])[F:43])[O:18][N:17]=3)=[CH:14][CH:15]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC(O)(c2ccc(C=NO)cc2)C1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(O)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 50 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a stirred solution of 3-hydroxy-3-[4-(hydroxyimino-methyl)-phenyl]-cyclobutane carboxylic acid ethyl ester (Preparation 2, 4.7 g, 17.87 mmol) in DMF (10 mL) was added N-chloro succinimide (2.61 g, 19.65 mmol) and heated at 50° C. for 1 hour. After complete consumption of starting material, reaction was cooled to 0° C., potassium hydrogen carbonate (2.68 g, 26.88 mmol) was added followed by addition of pre dissolved solution of 1,2,3-trichloro-5-(1-trifluoromethyl-vinyl)-benzene (5.40 g, 19.65 mmol). Resulting reaction mixture was stirred at room temperature for 16 hours. After consumption of chloro intermediate, reaction mixture was diluted with EtOAc (50 mL), washed with water (5×30 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. Purification was done by column chromatography (silica gel, 100-200 mesh). Compound was eluted using 15% ethyl acetate in hexane as eluent to afford white sticky solid (4.7 g, 49%). 1H NMR (400 MHz, CDCl3) δ 1.28 (t, J=9.36 Hz, 3H), 2.57-2.62 (m, 2H), 2.83-2.90 (m, 3H), 3.68 (d, J=17.28 Hz, 1H), 4.08 (d, J=17.16 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 7.55-7.57 (m, 2H), 7.64-7.67 (m, 4H). LC-MS (m/z): 536.10 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][CH:14]=[CH2:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CC(C)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:25][CH:24]=[CH2:23])=[C:8]([CH2:13][CH:14]=[CH2:15])[CH:7]=1
Reactant: C=CCBr
Reactant: C=CCc1cc(CCC(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(CCC(=O)OC)cc1CC=C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of methyl-3(3-allyl-4-hydroxyphenyl)propionate (12.3 g), anhydrous potassium carbonate (13.8 g), and allylbromide (8.64 mls) in acetone (300 ml) was stirred at ambient temperature for two days. The reaction mixture was filtered and the residue washed with acetone. The filtrate and washings were combined and evaporated to give methyl-3-(3-allyl-4-allyloxyphenyl)proprionate as a pale yellow oil (14.0 g); NMR: 2.58(2H,t), 2.75(2H,t), 3.31(2H,d), 3.55(3H,s), 4.52(2H,d), 4.95-5.45(4H,m), 5.85-6.11(2H,m), 6.85(1H,d) and 7.0(2H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F: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]([F:15])([F:17])[F:16])[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(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (322 mg, 1.0 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (242 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (247 mg, 51%). MS (ISP) 483.5 [(M+H)+]; mp 239–240° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[C:28]#[CH:29].O>CN(C=O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH2:29][C:28]#[CH:27])[N:12]=1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1nc(-c2ccc3ccccc3c2)c2c(N)ncnc21
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and propargylbromide were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 300.1, found 300.2
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][CH2:26][C:27](=O)[C:28](=O)[CH2:29][CH3:30]>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:28]([CH2:29][CH3:30])[C:27]([CH2:26][CH3:25])=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Reactant: CCC(=O)C(=O)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1nc2ccc3c(c2nc1CC)OC(COS(=O)(=O)c1ccc(C)cc1)CO3
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]-methyl 4-methylbenzenesulfonate (2.226 g, 5.258 mmole) in water (50 mL) was added a solution of 3,4-hexanedione (0.750 g, 6.572 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.796 g (80%) of the (R)-enantiomer of the title compound as a tan crystalline solid. Rf=0.85 (silica, ethyl acetate:hexanes 7:3); mp 132-135° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H-].[Na+].[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][S:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:28])=[O:27])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccccc4)cc23)CC1
Yield: 70.8 %

Procedure:
To a solution of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (4.75 g, 20.6 mmol) in dimethylformamide (25 mL), stirring at 0° C. under nitrogen, was added sodium hydride in one portion (0.83 g of a 60% dispersion in oil, 20.6 mmol). The green solution turned brown; after stirring for 30 minutes at 0° C. benzenesulfonyl chloride (2.63 mL, 20.6 mmol) was added in one portion, then the reaction mixture was allowed to stir until the reaction was complete. The solution was poured into water (125 mL), then extracted with ethyl acetate (4×125 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to a residue which was further purified on silica gel. Elution with a 9:1 mixture of dichloromethane and 2 N ammonia in methanol provided 5.40 g (70%) of benzenesulfonic acid 3-(1-methylpiperidin-4-yl)-1H-indol-5-yl ester as a tan solid: mp=189-194° C.; 1H NMR (400 MHz, dmso-d6): 10.97 (br s, 1H), 7.85-7.72 (m, 3H), 7.65-7.54 (mm, 2H), 7.24 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.0 Hz), 6.88 (d, 1H, J=1.2 Hz), 6.69 (dd, 1H, J=8.8, 1.6 Hz), 2.77 (br d, 2H, J=11.2 Hz), 2.52-2.40 (m, 1H), 2.16 (s, 3H), 1.91 (br t, 2H, J=11.2 Hz), 1.67 (br d, 2H, J=12.0 Hz), 1.58-1.44 (m, 2H); MS(ES+): m/e 371.0 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:4]=1.[C:18]([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)(N1C=CN=C1)=[O:19]>C1COCC1>[Si:11]([O:10][CH2:9][C:5]1[N:4]=[C:3]([CH2:2][NH:1][C:18]([NH:25][CH2:29][C:28]2[CH:2]=[CH:3][CH:8]=[C:26]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[N:27]=2)=[O:19])[CH:8]=[CH:7][CH:6]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CN)n1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CNC(=O)NCc2cccc(CO[Si](C)(C)C(C)(C)C)n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
2-Aminomethyl-6-[(tert-butyldimethylsilyloxy)methyl]pyridine (26) (380 mg, 1.50 mmol) and 1,1′-carbonyldiimidazole (150 mg, 0.92 mmol) were suspended in THF (10 mL). The air was evacuated from the reaction system, and then Ar was charged therein. The suspension was stirred for 24 hours at a room temperature. TLC was used to confirm there was no starting material in the mixture. Then, the reaction mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CDCl3:MeOH=50:1) to give N,N′-bis{[6-(tert-butyldimethylsilyloxy)methylpyridin-2-yl]methyl}urea (27) (384 mg, 96%) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=O.Cl.[NH2:13][NH:14][C:15]([NH2:17])=[O:16]>O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH:10]=[N:13][NH:14][C:15]([NH2:17])=[O:16]
Reactant: NNC(N)=O
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: Cl
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1C=NNC(N)=O
Yield: 93.8 %

Procedure:
In 180 ml. of hot water, 9.3 grams (0.06 mole) of 1-methyl-5-nitro-2-imidazolecarboxaldehyde is slurried while 6.7 grams (0.06 mole) of semicarbazide hydrochloride is added portionwise. After 15 minutes of heating, the mixture is cooled in a refrigerator overnight. The solid is then collected and washed with water and methanol, respectively, to give a yellow product, melting point 272°-273° C. (dec.). After drying at 100° for 2 hours under reduced pressure, 11.94 grams of 1-methyl-5-nitro-2-imidazolecarboxaldehyde semicarbazone is obtained. This semicarbazone (6.35 grams or 0.03 mole) is added to 10 grams of anhydrous sodium acetate in 50 ml. of glacial acetic acid and 1.25 ml. of bromine is added with continuous stirring. The mixture is heated gradually to give a nearly clear red solution at 50° C. which becomes increasingly turbid with time. After heating at 75° ± 3° for 3 hours, the mixture is cooled and poured on ice. The yellow solid is collected, washed with water, then with methanol, and dried under reduced pressure at 70°C. for 3 hours to give 5 grams of crude 2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-oxadiazole, melting point 284°-287° C. (dec.). This material is dissolved in boiling dimethylformamide, ethanol added, and the mixture cooled to give yellow crystals, melting point 291°-293° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)n1
Reactant: Brc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccc(Nc2ccccc2)n1
Yield: 35.7 %

Procedure:
To a flask were added 2.2 g of 2-amino-6-methylpyridine, 3.1 g of bromobenzene, 2.7 g of sodium tert-butoxide, and 50 ml toluene. The mixture was purged thoroughly with nitrogen and 62 mg of 2,2′-bis(diphenylphosphino)-1,1′-binaphthalenehthalene and 22 mg of palladium acetate were added. The reaction mixture was heated to 100 C for 16 hours, and then cooled to 22 C. After quenching with 50 ml water, the product was extracted with 20 ml ethyl acetate, and washed with 15 ml water. The product was extracted with 50 ml of 1M hydrochloric acid, and then basified with aqueous ammonium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using a gradient from 10% ethyl acetate in hexane to 15% ethyl acetate in hexane, resulting in 1.3 g of a yellow-orange oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:43])[C:32]4[CH:37]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[CH:35]=[CH:34][C:33]=4[Cl:42])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:39]([NH:38][C:36]1[CH:35]=[CH:34][C:33]([Cl:42])=[C:32]([CH:37]=1)[C:31]([NH:30][C:27]1[CH:26]=[N:25][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:29][CH:28]=1)=[O:43])(=[O:41])[CH3:40]
Reactant: CC(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
To a solution of intermediate 58 (Example 112) (0.25 g, 0.40 mmol) in DCM (8 mL) was added TFA (30% in DCM, 6 mL) and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated and the residue purified by HPLC to afford the title compound (TFA salt; 50 mg, 23%) as a white solid.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH:21](I)([CH3:23])[CH3:22]>>[CH:21]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:23])[CH3:22]
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Reactant: CC(C)I
Agent: [H-]
Agent: [Li+]
Product: CC(C)n1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 383 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.15 ml of isopropyl iodide were used. As a result, 144 mg of 3-isopropyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.