Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([C:16]([OH:18])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:32][NH2:33].O>C1COCC1>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([C:16]([NH:32][NH2:33])=[O:18])=[CH:5][N:4]=1
Reactant: CSc1ncc(C(=O)O)c(OCC[Si](C)(C)C)n1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CSc1ncc(C(=O)NN)c(OCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2-Methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carboxylic acid (9.73 g) obtained in Step 2 was dissolved in THF (100 mL), carbonyldiimidazole (5.5 g) was added thereto, followed by stirring at room temperature for 1.5 hours. Then, hydrazine monohydrate (4.70 mL) was added dropwise to the reaction mixture, and the resulting mixture was stirred at room temperature for 2.5 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was sequentially washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the mixture was dried under reduced pressure to give crude 2-methylthio-4-(2-trimethylsilylethoxy)pyrimidine-5-carbohydrazide [Compound (E) in which R1 is 2-trimethylsilylethoxy].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:19][N:18]([CH3:20])[C:17](=[S:21])[C:7]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[N:14][C:15]=3[C:6]=2[O:5]1.[CH3:22][NH:23][CH3:24]>>[ClH:1].[CH3:22][N:23]([CH3:24])[CH2:2][CH2:3][CH:4]1[CH2:19][N:18]([CH3:20])[C:17](=[S:21])[C:7]2[CH:8]=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[N:14][C:15]=3[C:6]=2[O:5]1
Reactant: CNC
Reactant: Cc1ccc2ccc3c(c2n1)OC(CCCl)CN(C)C3=S
Product: Cc1ccc2ccc3c(c2n1)OC(CCN(C)C)CN(C)C3=S
Product: Cl

Procedure:
Following the procedure of Example 31, 2-(2-chloroethyl)-2,3-dihydro-4,10-dimethyl-1,4-oxazepino[6,7-h]quinoline-5(4H)-thione is reacted with dimethylamine to give the title compound.
Reaction SMILES: F[C:2]1[C:11]2[O:10][CH:9]([C:12]([NH2:14])=[O:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:15]C1C2OCCNC=2C=CC=1.CCC([O-])=O>>[Cl:15][C:2]1[C:11]2[O:10][CH:9]([C:12]([NH2:14])=[O:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c1OCCN2
Reactant: NC(=O)C1CNc2cccc(F)c2O1
Agent: CCC(=O)[O-]
Product: NC(=O)C1CNc2cccc(Cl)c2O1

Procedure:
This compound is obtained using the same experimental conditions as those used for the synthesis of intermediate 4b but replacing 3,4-dihydro-8-fluoro-2H-1,4-benzoxazine-2-ethyl carboxylate (5b) with 3,4-dihydro-8-chloro-2H-1,4-benzoxazine-2-ethyl carboxylate (5d), [73268-47-0]. The title compound of formula (4d) is obtained.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[H-].[Na+].[Cl:16][CH2:17][CH2:18][CH2:19]Cl>CN(C=O)C>[CH2:1]([N:3]([CH2:19][CH2:18][CH2:17][Cl:16])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCNS(=O)(=O)c1ccc(C)cc1
Reactant: ClCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CCCCl)S(=O)(=O)c1ccc(C)cc1
Temperature: 53 °C
Yield: 42 %

Procedure:
To N-ethyl-p-toluenesulfonamide (5.01 g, 0.0251 mol) in DMF (50 mL) in a dry flask is added sodium hydride (80% in oil, 0.93 g, 0.031 mol). After gas evolution subsides, 1,3-dichloropropane (22.48 g, 0.199 mol) is added. The mixture is heated at 53° C. for 10 h then cooled and poured into ice water (300 mL), which is extracted twice with ether. The combined extracts are washed with 1% sodium bisulfite, water (3×), and brine. Removal of solvent by rotary evaporation then Kugelrohr distillation gives crude product, which is chromatographed on silica gel (30% hexane/CHCl3) to furnish 2.91 g product (42%) NMR (CDCl3) δ1.15 (t, 3H), 1.9-2.2 (m, 2H), 2.44 (s, 3H), 3.11-3.35 (m, 4H), 3.6 (t, 2H), 7.3 (d, 2H ), 7.74 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][NH:7][C:8]1[NH:13][CH2:12][C:11]2=[C:14]([CH3:20])[N:15]=[C:16]([CH2:17][CH2:18][CH3:19])[N:10]2[N:9]=1.C(O)(=O)/C=C\C([O-])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]2=[C:14]([CH3:20])[N:15]=[C:16]([CH2:17][CH2:18][CH3:19])[N:10]2[N:9]=1
Reactant: CCCc1nc(C)c2n1N=C(NCc1ccc(OC)c(OC)c1)NC2
Agent: O=C([O-])/C=C\C(=O)O
Product: CCCc1nc(C)c2cnc(NCc3ccc(OC)c(OC)c3)nn12

Procedure:
2-(3,4-Dimethoxybenzylamino)5-methyl-7-propylimidazo[5,1-f]-as-triazine, m.p. 158°-160° was prepared from 2-(3,4-dimethoxybenzylamino)3,4-dihydro-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 12d). It was converted to its hydrogen maleate, m.p. 118°-121°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][N:20]2[CH:25]3[CH2:26][CH2:27][CH:21]2[CH2:22][N:23]([C:28]([O:30]C(C)(C)C)=O)[CH2:24]3)[NH:12][C:11]([C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[N:10]1.F[C:41](F)(F)C(O)=O>ClCCl>[C:28]([N:23]1[CH2:24][CH:25]2[N:20]([CH2:19][C:13]3[NH:12][C:11]([C:35]4[S:36][CH:37]=[CH:38][N:39]=4)=[N:10][C@@H:9]([C:3]4[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=4[Cl:1])[C:14]=3[C:15]([O:17][CH3:18])=[O:16])[CH:21]([CH2:27][CH2:26]2)[CH2:22]1)(=[O:30])[CH3:41]
Reactant: COC(=O)C1=C(CN2C3CCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=C(CN2C3CCC2CN(C(C)=O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (80 mg), trifluoroacetic acid (1.0 mL) and dichloromethane (2.0 mL) was stirred at room temperature for one hour, and then concentrated. The residue was dissolved in dichloromethane (5.0 mL), followed by adding diisopropylethylamine (0.2 mL) and acetic chloride (0.1 mL). The result mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by prep-HPLC to give Methyl (4R)-6-[(3-acetyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 122 (11.3 mg).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH3:10])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][C:46]1[CH:55]=[C:54]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:55]=[C:54]([N:56]2[CH2:61][CH2:60][N:59]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH:2]([CH3:1])[CH2:8][CH2:9][CH3:10])[CH2:58][CH2:57]2)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=1
Reactant: CCCC(C)/C=C/C(=O)O
Reactant: COc1cc(N2CCNCC2)c2ccccc2n1
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: CCCC(C)/C=C/C(=O)N1CCN(c2cc(OC)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
(E)-4-Methyl-hept-2-enoic acid (21.3 mg, 0.15 mmol) was dissolved in DMF (350 μl), diisopropylethylamine was added (26 μl, 0.15 mmol) followed by HATU (57 mg, 0.15 mmol dissolved in 0.25 ml DMF). The mixture was stirred at room temperature for 15 minutes, then 2-methoxy-4-piperazin-1-yl-quinoline (36.4 mg, 0.15 mmol, dissolved in 1 ml DMF) was added and stirring was continued overnight. The mixture was evaporated under reduced pressure, the residue was dissolved in dichloromethane and the resulting solution was washed with 5% sodium bicarbonate solution, water, evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 21.1 mg (0.06 mmol, 39.8%) of a solid.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH3:27])[CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](N1C=C(CO)C=N1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].ICC.CC1C(CCOC)=C(C)N(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)N=1>>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:22]=[N:21]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: COCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: COCCc1c(C)nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Product: CCOCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 87 %

Procedure:
This compound is a slightly yellow solid and has been obtained as described in 2b for 1-trityl-4-methoxymethylpyrazole, starting from 1-trityl-4-hydroxymethylpyrazole (1.250 g; 3.67 mmol), sodium hydride (221 mg; 5.51 mmol) and iodoethane (1.5 mL; 18.35 mmol), as described in example 2a for 3,5-dimethyl-4-methoxyethyl-1-tritylpyrazole. Yield: 87% (1.174 g, 3.19 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[CH:10]=[N:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 4-chlorobenzene-1-sulfonyl chloride.
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH3:21])[CH:16]=3)[CH2:11]2)[C@:6]1([CH3:26])[CH2:22][C:23]([OH:25])=[O:24])(=O)C.[OH-].[K+]>CO.O>[CH3:21][O:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([C@H:7]1[C@:6]([CH3:26])([CH2:22][C:23]([OH:25])=[O:24])[C@@H:5]([OH:4])[CH2:9][CH2:8]1)[CH2:19][CH2:18]2
Reactant: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](OC(C)=O)[C@@]1(C)CC(=O)O)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CCC([C@@H]1CC[C@H](O)[C@@]1(C)CC(=O)O)C2

Procedure:
To a solution of 3.33 g of (1S,2S,5S)-2-acetoxy-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-1-methylcyclo-pentaneacetic acid in 50 ml of methanol is added a solution of 3.00 g of potassium hydroxide in 15 ml of water. The resultant solution is refluxed for 2 hours, then diluted with 250 ml of water. Clarification is effected by filtration. The filtrate is acidified with hydrochloric acid. A solid precipitates which, isolated by filtration and recrystallized from a mixture of ethyl acetate and hexane, affords (1S,2S,5S)-5-(1,2,3,4-tetrahydro-6-methoxy-2-naphthyl)-2-hydroxy-1-methylcyclopentaneacetic acid melting at approximately 141.5°-142.5°. The product has a specific rotation of +65°.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:45]4[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=4[N:43]=3)=[CH:38][CH:37]=2)=[CH:32][CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[C:31]([C:36]5[CH:41]=[CH:40][C:39]([C:42]6[N:46]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)[C:45]7[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=7[N:43]=6)=[CH:38][CH:37]=5)=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccccc1-c1ccccc1-c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-n2c(-c3ccc(-c4ccccc4-c4ccccc4-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)nc3ccccc32)cc1

Procedure:
Following the procedure for Host-1, (9-phenyl-9H-carbazol-3-yl)boronic acid (0.458 g, 1.60 mmol), Compound 3 (0.800 g, 1.60 mmol), tetrakis(triphenylphosphine)palladium(0) (73.7 mg, 63.8 μmol), Na2CO3 (0.530 g, 5.00 mmol), H2O (5 mL) and 1,4-dioxane (25 mL) provided Host-2 (0.78 g, 74%) as an off-white solid after flash chromatography (SiO2, 17:3-hexanes: acetone) and recrystallization from methanol (CH3OH): confirmed by LCMS (APCI): calculated for C49H33N3 (M+): 664; Found: 664.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]=[C:10]([C:25](=O)[CH3:26])[C:11]([O:13][C@@H:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12].[NH2:28][C:29]([CH2:35][F:36])=[CH:30][C:31]([O:33][CH3:34])=[O:32]>C(O)(C)(C)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:11]([O:13][C@@H:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15]([Cl:18])([Cl:17])[Cl:16])=[O:12])=[C:25]([CH3:26])[NH:28][C:29]([CH2:35][F:36])=[C:30]1[C:31]([O:33][CH3:34])=[O:32]
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(=O)O[C@@H](c1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)C=C(N)CF
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)O[C@@H](c2ccccc2)C(Cl)(Cl)Cl)C1c1cccc(Cl)c1Cl

Procedure:
(S)-2,2,2-Trichloro-1-phenylethyl 2-(2,3-dichlorophenylmethylene)-3-oxobutanoate (10.8 g, 23 mmoles) and methyl 3-amino-4-fluoro-2-butenoate (3.7 g, 28 mmoles) were heated at 55° in dry tert-butanol (50 ml) for 68 hours. The solvent was removed and the residue purified and separated into single diastereomers by HPLC eluting with methylene chloride/petroleum ether (60°-80° ) mixtures.
Reaction SMILES: C[O:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21]C)=[C:16]([O:19]C)[CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:26]>C(Cl)Cl>[BrH:26].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([OH:19])[CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:23][CH:24]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(OCC2NCCc3cc(OC)c(OC)cc32)cc1
Solvent: ClCCl
Product: Br
Product: Oc1ccc(OCC2NCCc3cc(O)c(O)cc32)cc1

Procedure:
To a solution of 1-(4-methoxyphenoxy)methyl-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline (100 mg) in anhydrous methylene chloride (5 ml) was added a solution of boron tribromide (300 mg) in anhydrous methylene chloride (0.6 ml) at -51° C. under cooling and stirring, and the mixture was stirred for 19 hours at -51° to -20° C. After the reaction, methylene chloride was distilled off under reduced pressure. To the residue were added methanol (5 ml) and water (0.5 ml) and the mixture was warmed, and then the solvent was distilled off under reduced pressure. The colourless powderly residue was dissolved in acetone, and then to the solution was added ether, and the mixture was allowed to stand. The precipitated crystals were collected by filtration to give colourless powder of 1-(4-hydroxyphenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1>CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:22]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
1-Bromo-4-chloro-2-nitro-benzene (7.00 g, 29.60 mmol) was dissolved in DMF to which K2CO3 (5.11 g, 37.01 mmol) and 3-Hydroxy-benzoic acid methyl ester (4.95 g, 32.57 mmol) were added. The reaction mixture was then heated to 100° C. for 2 h the reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate. Solvent dried over Na2SO4, filtered and concentrated under vacuum giving the title compound. (7.2 g, 79%)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([CH3:18])[CH:8]=1)=O.Cl.[S:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1)(=[O:26])(=[O:25])[NH2:24]>C(O)C>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:33]([C:30]3[CH:29]=[CH:28][C:27]([S:23]([NH2:24])(=[O:26])=[O:25])=[CH:32][CH:31]=3)[N:34]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=2)=[CH:8][C:9]=1[CH3:18]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Agent: Cl
Solvent: CCO
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)ccc1-c1ccco1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
To a stirred soluition of 4,4,4-trifluoro-1-[4-(2-furyl)-3-methylphenyl]butane-1,3-dione (0.53 g, 1.80 mmol) in ethanol (22.5 ml) was added (4-sulfamoylphenyl)hydrazine hydrochloride (0.44 ml, 1.98 mmol), and the mixture was heated at reflux temperature for 16 hours. The mixture was cooled down to room temperature, and concentrated in vacuo. The residue was dissolved in ethyl acetate. washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1/3). The resulting solid was recrystallized with dichloromethane-hexane to give the title compound (0.16 g, 20% yield).
Reaction SMILES: [C:1]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N([CH2:23][CH3:24])CC)C.[P:25](=[O:34])(Cl)([S:29][CH2:30][CH2:31][CH3:32])[O:26][CH2:27][CH3:28]>C(#N)C>[CH2:27]([O:26][P:25]([O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:10][P:25]([S:29][CH2:30][CH2:23][CH3:24])([O:26][CH2:27][CH3:28])=[O:34])=[CH:8][CH:9]=2)([CH3:3])[CH3:2])=[CH:16][CH:15]=1)([S:29][CH2:30][CH2:31][CH3:32])=[O:34])[CH3:28]
Reactant: CCN(CC)CC
Reactant: CCCSP(=O)(Cl)OCC
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CC#N
Product: CCCSP(=O)(OCC)Oc1ccc(C(C)(C)c2ccc(OP(=O)(OCC)SCCC)cc2)cc1
Temperature: 10 °C
Yield: 54 %

Procedure:
To a 250 ml round bottom flask equipped with a water condenser, drying tube, magnetic stirrer, and addition funnel was added 4,4'-isopropylidenediphenol (4.57 g, 20 mmol), triethylamine (4.24 g, 42 mmol), and acetonitrile (75 ml). The solution was cooled to 10° C. and O-ethyl S-n-propyl phosphorochloridothioate (8.30 g, 41 mmol) in acetonitrile (25 ml) was added dropwise over 15 minutes. The cooling bath was removed and the reaction warmed to 35° C. for 4 hours. The reaction was diluted with ether (500 ml) and washed successively with water (2×50 ml), 1M NaOH (2×50 ml), 1% HCl (2×50 ml), and brine (2×50 ml). The organic solution was dried (MgSO4) and concentrated under reduced pressure to give the desired product as a colorless oil (6.50 g, 10.8 mmol).
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Cl)[N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[Cl:18][C:19]1[N:20]=[C:21]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc(Cl)n1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Clc1cccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)n1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2,6-dichloropyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). MW: 331.81; mp: 122.0-123.0° C.; 1H-NMR (DMSO) δ: 8.22 (1H, t, J=7.9 Hz), 7.91 (1H, d, J=16.1 Hz), 7.79-7.72 (3H, m), 7.67-7.63 (2H, m), 7.50-7.47 (1H, m), 746-7.28 (5H, m), 7.23 (1H, d, J=16.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.[Cl-].[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH3+:28])[CH:23]=[C:22]2[CH3:29].CN1CCOCC1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>O.CN(C=O)C>[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([NH:28][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[CH:23]=[C:22]2[CH3:29]
Reactant: Cc1nc(-c2ncccn2)ncc1C(=O)O
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1nc(-c2ncccn2)ncc1C(=O)Nn1cc(C)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
4-Methyl-[2,2]bipyrimidinyl-5-carboxylic acid (0.5 g, 2.31 mmol) is combined with 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (464 mg, 2.31 mmol), N-methylmorpholine (233 mg, 2.31 mmol) and DMF (10 mL). The suspension is stirred for 5 minutes at rt, then 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride is added (640 mg, 2.31 mmol). The reaction is heated to 50° C. for 4 h. The reaction is then poured into water (50 mL), the suspension is chilled for 2 h in the refrigerator, and then filtered. The solids are then suspended in acetonitrile at 50° C. for 4 h, cooled, then filtered to afford 4-methyl-[2,2′]bipyrimidinyl-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (60%). MS: 363 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 2.77 (s, 3H), 7.07 (dt, 1H), 7.36 (dd, 1H), 7.38 (s, 1H), 7.44-7.48 (m, 1H), 7.70 (t, 1H), 9.05 (d, 2H), 9.29 (s, 1H), 11.9 (s, 1H). IC50=4.5 nM.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][C:12]#[N:13]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH3:13].[Cl:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][NH2:13]
Reactant: N#CCc1ccc(F)cc1Cl
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N
Product: NCCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (1.73 g, 45.51 mmol) was added portionwise to a solution of 2-chloro-4-fluorophenylacetonitrile (1.04 g, 6.15 mmol) and cobalt (II) chloride hexahydrate (2.18 g, 9.22 mmol) in methanol (30 mL) and the mixture was stirred at room temperature for 3 hours. The suspension was then filtered though Celite®, concentrated in vacuo and the residue was partitioned between 1M hydrochloric acid (40 mL) and dichloromethane (40 mL). The aqueous phase was separated, basified to pH 11 with 1M ammonia solution and extracted with dichloromethane (2×40 mL). The combined organic solution was washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 98:2:0.2, to afford the title compound as a yellow oil, 350 mg.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([N:30]1CCCCC1=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:23]([N:30]1[CH2:3][CH2:2][CH:1]([NH:6][C:7]2[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12]3)[CH2:5][CH2:4]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: Cc1cc(NC2CCCC2)c2[nH]c(-c3ccccc3)cc2c1
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c2[nH]c(-c3ccccc3)cc2c1

Procedure:
7-Amino-5-methyl-2-phenyl-1H-indole prepared in Example 2 and 1-BOC-piperidinone were reacted according to the same procedure as Preparation 23 to give the title compound.