Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]=[CH:7][CH:8]=[CH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([CH:6]=[CH:7][CH:8]=[CH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C=CC=Cc1cccc2cncn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C=CC=Cc1cccc2cncn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 200 mg of 5-(4-ethoxycarbonylbuta-1,3-dienyl)imidazo[1,5-a]pyridine in 20 ml of methanol is added 4 ml of 1N sodium hydroxide. The reaction mixture is stirred at room temperature for 18 hours. The methanol is evaporated under reduced pressure and the residue diluted with 20 ml of water and the solution is adjusted to pH 5 with hydrochloric acid. The precipitate is collected to give 5-(4-carboxybuta-1,3-dienyl)-imidazo[1,5-a]pyridine, melting at 243°-245°.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[C:9]2[C:4](=[C:5]3[CH:23]=[CH:22][CH:21]=[CH:20][C:6]3=[CH:7][CH:8]=2)[NH:3]1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:24]1[C:15]([C:14]2[CH:13]=[C:12]([CH:10]3[C:9]4[C:4](=[C:5]5[CH:23]=[CH:22][CH:21]=[CH:20][C:6]5=[CH:7][CH:8]=4)[NH:3][C:2](=[O:1])[CH2:11]3)[CH:19]=[CH:18][CH:17]=2)=[N:16][N:26]=[N:25]1
Reactant: N#Cc1cccc(C2CC(=O)Nc3c2ccc2ccccc32)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC(c2cccc(-c3nnn[nH]3)c2)c2ccc3ccccc3c2N1
Temperature: 130 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
A mixture of 3-(2-Oxo-1,2,3,4-tetrahydro-benzo[h]quinolin-4-yl)-benzonitrile (0.50 g, 1.68 mmol), sodium azide (0.13 g, 2.0 mmol) and ammonium chloride (0.11 g, 2.01 mmol) in dimethylformamide (3.5 ml) was heated with stirring at 130° C. for 18 hr. The solvent was removed in vacuo and water was added. The solution was acidified with dilute hydrochloric acid to afford a precipitate which was separated by filtration. Crystallization from methanol afforded the title compound (0.23 g, 0.67 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[CH:31]2)[CH:18](N1C(=O)CCC1=O)O>C(O)(C)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH2:27][C:28]4[CH:29]=[C:30]5[C:35](=[CH:36][CH:37]=4)[N:34]=[CH:33][CH:32]=[CH:31]5)=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: O=C1CCC(=O)N1C(O)C(Cl)Cc1ccc2ncccc2c1
Solvent: O
Solvent: CC(C)O
Product: Fc1cc(-c2cnc3ncc(Cc4ccc5ncccc5c4)n3n2)ccc1Br
Temperature: 105 °C
Yield: 55.8 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (Step 5, 200 mg, 0.743 mmol) and 1-(2-chloro-1-hydroxy-3-quinolin-6-ylpropyl)pyrrolidine-2,5-dione (Step 7, 284 mg, 0.892 mmol) in isopropyl alcohol (7.4 mL) and water (0.11 mL) in a sealed tube was heated at 105° C. for 5 d. After the reaction mixture was cooled to ambient temperature, the precipitate was collected by filtration, washed with isopropanyl alcohol, and dried in vacuum to give the desired product (180 mg, 55%) LCMS (M+H)+: m/z=433.9/436.0.
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([NH2:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.O.[NH2:18][NH2:19]>CO>[N:18](=[C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([NH2:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1)[NH2:19]
Reactant: NN
Reactant: CC1CCC(Br)c2ncc(C(N)=O)c(=O)n21
Solvent: CO
Solvent: O
Product: CC1CCC(=NN)c2ncc(C(N)=O)c(=O)n21
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
In 150 ml. of methanol 10.0 g. (34.95 millimoles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide are dissolved under heating. To the solution 20 ml. hydrazine hydrate are added dropwise under stirring carefully within 10 minutes. The reaction mixture is heated to boiling for 40 minutes whereupon the methanol is distilled off in vacuo. The crystals are filtered off, washed with water and crystallized from water. Thus 3.8 g. (46.5%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide are obtained. Mp.: 248°-250° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([C:8]([C:20]#[N:21])([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)C(OCC)=O)[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:8]([CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1cccs1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(Cc1cccs1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-Amino-α-cyano-1,6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidineacetic acid, ethyl ester as prepared above (5.0 g) in 1N NaOH (200 mL) is stirred at room temperature for 90 min. The reaction mixture is acidified to pH 1 with 4N HCl and stirred for 5 min. The reaction mixture is neutralized (pH 7) with 1N NaOH and the product 2-Amino-1,6-dihydro-5-nitro-6-oxo-α-(2-thienylmethyl)-4-pyrimidineacetonitrile (4.1 g, 98%) is collected by filtration. ##STR15##
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH:20]1([CH2:19][CH2:18][S:17][C:9]2[N:8]([CH2:7][C:6]([OH:26])=[O:5])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)Cn1c(SCCC2CCCCC2)nc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(SCCC2CCCCC2)nc2ccccc21
Yield: 29 %

Procedure:
A solution of tert-butyl[2-(2-cyclohexyl-ethylsulfanyl)-benzoimidazol-1-yl]-acetate (Precursor A-01b, 42 mg, 0.13 mmol) in TFA/dichloromethane (1:1, 0.5 ml) is stirred at rt for 4 h. The solvents are removed in vacuo. The crude residue is sonicated in Et2O/heptane (1:1, 1 ml) until a solid precipitates. It is rinsed with heptane and purified by flash chromatography on silica gel (AcOEt/heptane, 1:1 containing 1% of AcOH), yielding the title compound (12 mg) in 30% as a white solid: tR=6.44 min (LC-1), ESI-MS (pos.): m/z 319.12 [M+H]+, ESI-MS (neg.): m/z 317.37 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 0.82-0.94 (m, 2H), 1.09-1.23 (m, 3H), 1.37 (m, 1H), 1.54 (q, 2H, SCH2CH2), 1.68 (m, 5H), 3.34 (t, 2H, SCH2), 4.88 (s, 2H, CH2CO2), 7.22 (s, 3Harom), 7.65 (m, 1Harom).
Reaction SMILES: [Li][CH3:2].[CH3:3][C:4](=[O:25])[C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C@H:12]([CH2:13][C:14](=[O:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1>C1(C)C=CC=CC=1>[CH3:3][C:4]([C@@H:5]1[C@@:22]2([CH3:23])[CH2:21][CH2:20][C@@H:19]3[C@@:17]4([CH3:18])[CH2:16][CH2:15][C@:14]([OH:24])([CH3:2])[CH2:13][C@@H:12]4[CH2:11][CH2:10][C@H:9]3[C@@H:8]2[CH2:7][CH2:6]1)=[O:25]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: [Li]C
Solvent: Cc1ccccc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -25 °C
Reaction time: 5 h

Procedure:
Ferrous chloride (4 g) is reacted with MeLi (3 equiv. based on FeCl2) in toluene (anhydrous, 200 mL) at −25° C. under nitrogen. 5α-pregnane 3,20-dione (10 g) is then added to this mixture. The mixture is stirred at −25° C. for 5 h. It is quenched by adding acetic acid (32 mL). The mixture is concentrated in vacuo and the residue is stirred in 3N HCl (200 mL) for 6 h. The solid is collected by filtration, washed with water and dried. The crude product is dissolved in THF (33 mL) at reflux and filtered hot. The filtrate is mixed with water (45 mL) and the solid is collected by filtration, washed with water and dried. The solid is further slurried in ethyl acetate (50 mL) at 70° C. for 8 h. It is cooled to 5° C. and filtered, washed with cold ethyl acetate and dried to obtain ganaxolone.
Reaction SMILES: C1(O[C:8](=[O:23])[NH:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:13]([C:21]#[N:22])=[CH:12][N:11]=2)C=CC=CC=1.C(C1C=CC(NC([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][C:44]([CH:46](OC)[O:47]C)=[N:45][C:36]2=3)=O)=NC=1)#N>>[C:21]([C:13]1[C:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:15][C:10]([NH:9][C:8]([N:35]2[CH2:41][CH2:40][CH2:39][CH2:38][C:37]3[CH:42]=[CH:43][C:44]([CH:46]=[O:47])=[N:45][C:36]2=3)=[O:23])=[N:11][CH:12]=1)#[N:22]
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCCC2
Product: COCCOc1cc(NC(=O)N2CCCCc3ccc(C=O)nc32)ncc1C#N

Procedure:
From intermediates 108 and 237, coupled and deprotected in an analogous manner to intermediate 236 and Example 201. The title compound was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[N:4][N:3]=1.[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1>N1C=CC=CC=1>[I:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:1][C:2]2[S:6][C:5]([S:7](=[O:9])(=[O:8])[NH2:10])=[N:4][N:3]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: Nc1nnc(S(N)(=O)=O)s1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1nnc(NC(=O)c2ccc(I)cc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
To a solution of 5-amino-1,3,4-thiadiazole-2-sulfonamide (0.133 g, 0.50 mmol) in pyridine (5.0 mL) was added 4-iodobenzoyl chloride (0.162 g, 0.75 mmol). The reaction mixture was stirred at room temperature for overnight under nitrogen. Solvent was concentrated and water (60 mL) was added the mixture. The precipitated sulfonamide was filtered and dried over vacuum to give desired compound (27.3 mg, 13%) as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([C:40]3([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:43][O:42][CH2:41]3)=[CH:36][CH:35]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:20]1([C:3]2[N:4]=[C:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[NH:9][C:8]4[N:16]=[CH:17][CH:18]=[CH:19][C:7]=4[N:6]3[C:2]=2[C:34]2[CH:35]=[CH:36][C:37]([C:40]3([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:43][O:42][CH2:41]3)=[CH:38][CH:39]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)COC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A suspension of 3-bromo-2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (50 mg) and tert-butyl {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl}carbamate (96 mg) and potassium phosphate (82 mg) and PdCl2(dppf)CH2Cl2 (11 mg) in dioxane (2.5 mL) and H2O (0.25 mL) was degassed for 5 min then stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (5-100% ethyl acetate in hexanes) gave the product (58 mg, 81%). 1HNMR (DMSO-d6) 400 MHz δ: 8.57 (s, 1H), 8.16-7.83 (m, 3H), 7.55-7.44 (m, 4H), 7.39-7.21 (m, 7H), 7.15-7.09 (m, 1H), 6.98-6.84 (m, 1H), 6.68 (dd, J=7.8, 4.6 Hz, 1H), 4.87-4.75 (m, 2H), 4.73-4.60 (m, 2H), 1.57-1.03 (m, 9H). LCMS: 558 [M+H].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:14][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(NC(=O)c2cccs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
According to Scheme 1 Method A: A solution of thiophene-2-carbonyl chloride (2.92 mmol, 0.31 mL) in DCM (1 mL) was added to solution of 3-methoxyaniline (2.44 mmol, 0.27 mL) and DIEA (4.87 mmol, 0.87 mL) in DCM (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The organic phase was washed with HCl 1 M solution, then with a saturated solution of NaHCO3, was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield N-(3-methoxyphenyl)thiophene-2-carboxamide (1.71 mmol, 0.40 g, 70%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:35])[C@@H:18]([NH:27]C(=O)OC(C)(C)C)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)[C:3]1=[O:36].Cl.[Cl:39][Si](C)(C)C.CO>C(OCC)C>[ClH:39].[NH2:27][C@@H:18]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:17]([N:14]1[CH2:13][CH2:12][CH:11]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:37])([CH3:1])[C:3]2=[O:36])[CH2:16][CH2:15]1)=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N1CCC(N2C(=O)C(C)(C)c3ccccc32)CC1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC1(C)C(=O)N(C2CCN(C(=O)[C@@H](N)CCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A mixture of (S)-tert-butyl 1-(4-(3,3-dimethyl-2-oxoindolin-1-yl)piperidin-1-yl)-1-oxo-4-phenylbutan-2-ylcarbamate (2.79 g, 5.52 mmol, EXAMPLE 1, Step 3) and 1 mol/L hydrochloride in diethyl ether (25 mL) was stirred at room temperature. After 4 h, a mixture of chlorotrimethylsilane (2 mL) and methanol (4 mL) was added to the reaction suspension. The whole mixture changed to a clear solution and was stirred for 3 h. The mixture was concentrated in vacuo and the residue was diluted with diethyl ether and re-concentrated to remove methanol completely. The obtained solid was washed with diethyl ether to give the title compound (2.05 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:17]>C(O)C>[ClH:17].[CH:9](=[C:4]1[C:5](=[O:8])[C:6](=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][N:2]([CH3:1])[CH2:3]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CN1CC(=Cc2ccccc2)C(=O)C(=Cc2ccccc2)C1
Reaction time: 16 h

Procedure:
A solution of 57.0 g of 1-methyl-4-piperidone and 106.0 g of benzaldehyde in 400 ml of ethanol is cooled in an ice-bath and treated with hydrogen chloride gas until 250 g is absorbed. The solution is allowed to stand at room temperature for about 16 hours. The resulting solution is seeded, allowed to stand for about 16 hours at room temperature and the crystalline solid filtered on a sintered-glass funnel and washed with cold ethanol and then with ether. After drying in a desiccator, the solid (146 g) is digested in 400 ml of hot ethanol, cooled and filtered to give 120 g of product, melting point 242°-244° C, dec. Recrystallization of 11 g of this material from 35 ml of dimethylformamide gives 9.2 g of product, melting point 242°-244° C, dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6](/[CH:8]=[N:9]/[NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:9]=[CH:8]2
Reactant: Fc1ccc(N/N=C/c2cc(Br)ccc2F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Temperature: 220 °C
Yield: 99.8 %

Procedure:
A 30 mL microwave vial was charged with 3.00 g (9.642 mmol) of N-[1-(5-bromo-2-fluorophenyl)meth-(E)-ylidene]-N′-(4-fluorophenyl)hydrazine and 3.14 g (9.64 mmol) of cesium carbonate and 10 mL of DMSO and sealed. The mixture was warmed at 220° C. in the microwave for 15 minutes cooled and opened at room temperature. The mixture was diluted with 10 mL of water and extracted with 20 mL of EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was absorbed onto silica gel and passed through a silica pad and eluted with 50% EtOAc-hexanes. The partially purified material from the pad was triturated with MeOH, collected by filtration, and dried to afford 2.8 g (99.7%) of 5-bromo-1-(4-fluorophenyl)-1H-indazole. MS m/z 279.11 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:20]=1.[S:21]([OH:25])([OH:24])(=[O:23])=[O:22].CS[C:28](=[NH:30])[NH2:29]>CN(C)C=O.O>[S:21]([OH:25])([OH:24])(=[O:23])=[O:22].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:28](=[NH:29])[NH2:30])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:20]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][N:17]([C:28](=[NH:29])[NH2:30])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:20]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCNCC1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: O
Product: N=C(N)N1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a solution of 5-chloro-3-[(1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (3.0 g) in a mixture of N,N-dimethylformamide (30 ml) and water (5 ml) was added S-methylisothiourea sulfate (4.0 g). The mixture was stirred for 8 hours at 80° C. and then cooled. The precipitates formed were filtered and recrystallized from water (100 ml) to give 5-chloro-3-[(4-amidino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hemisulfate (2.63 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:18])[CH2:16][N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:15])=[C:6]2[C:5]1=[O:17]>CO>[CH3:3][C:4]1([CH3:18])[CH2:16][N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([CH3:15])=[C:6]2[CH:5]1[OH:17]
Reactant: Cc1c2n(c3ccccc13)CC(C)(C)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c2n(c3ccccc13)CC(C)(C)C2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Sodium borohydride (1.93 g, 50.7 mmole) was added portionwise upon mild cooling to a solution of 2,3-dihydro-2,2,9-trimethyl-1H-pyrrolo[1,2-a]indol-1-one (3.62 g, 16.9 mmole) in methanol (80 mL). The reaction mixture was stirred at 25° C. overnight. The solvent was removed in vacuo, and the residue was suspended in water (80 mL). The product was extracted with chloroform (3×50 mL). The combined organic layers were washed with brine (50 mL), then dried over MgSO4, filtered, and evaporated to dryness in vacuo to afford 3.49 g (96%) of product, m.p. 82°-85° C., as a light amber solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[NH2:18][CH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:19]1([NH:18][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH2:12][CH2:13]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: NC1CCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1ccc2c(c1)CCC2NC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.7 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and 1-aminoindan (67 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (17 mg) and a syn-form compound (18 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1[NH:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][N:14]=2)[O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.CCN(C(C)C)C(C)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[O:4][CH:3]1[CH2:2][NH:1][C:30](=[O:32])[N:12]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:19]=[C:11]12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCC(OC1CCCCO1)c1cc2cccnc2[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCC(OC2CCCCO2)c2cc3cccnc3n21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 210.9 %

Procedure:
A solution of 9a (7.4 g, 28 mmol) and DIPEA (5 ml, 28 mmol) in CH2Cl2 (300 ml) was slowly added to a solution of triphosgene (2.82 g, 10 mmol) in CH2Cl2 (740 ml) and the mixture was stirred at room temperature for 30 min. The organic mixture was washed with saturated aq. NH4Cl and with water. The organic solution was dried and evaporated to give a diastereomeric mixture (1:1) of 10a (6.06 g, 76%).
Reaction SMILES: [C:1]([C:4]1[C:24]([CH3:25])=[CH:23][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C([O-])(O)=[O:27].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:4]1[C:24]([CH3:25])=[CH:23][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][N:14]=3)=[O:27])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccnc(CSc2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccnc(CS(=O)c2nc3cc(C(C)=O)c(C)cc3[nH]2)c1OC
Reaction time: 0.17 h

Procedure:
5-Acetyl-6-methyl-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (3.75 g, 10 mmol) was dissolved in CH2Cl2 (70 ml). NaHCO3 (1.76 g, 21 mmol) in H2O (25 ml) was added and the mixture was cooled to ≈+3° C. m-Chloroperbenzoic acid 69.5% (2.43 g, 9.8 mmol) dissolved in CH2Cl2 (20 ml) was added dropwise under stirring. Stirring was continued for 10 min. The phases were separated and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was crystallized from CH3CN giving the title compound (2.25 g, 60%).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[CH:10][CH:9]=1)(C)[C:3]([NH2:5])=O.O.Cl>C1COCC1>[CH3:18][CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]([CH3:1])[CH2:3][NH2:5])=[CH:9][CH:10]=1)[CH2:16][CH3:17]
Reactant: CCC(C)Oc1ccc(OC(C)(C)C(N)=O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)Oc1ccc(OC(C)CN)cc1
Reaction time: 48 h

Procedure:
To the above propanamide (1.32 g, 5.6 mmol) in 10 ml of THF at 0° is added dropwise 0.97 M BH3 -THF (35 ml) over 40 min. The solution is heated under reflux overnight and is then allowed to sit at RT for 48 hours, after which 10 ml of water is added dropwise over 30 min., followed by dropwise addition of 20 ml of aqueous 5N HCl. The THF is removed by distillation, and the aqueous phase is saturated with NaOH pellets and extracted with ether (3×). The combined organic layers are washed with water and with brine, dried and solvent removed to give 2-[4-(1-methylpropoxy)phenoxy]propylamine.