Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:4][C:5]([N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH3:24][C:25]1([CH3:41])[O:30][C@@H:29]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][C@@H:27]([CH:39]=[CH2:40])[O:26]1.C1(CNCC2CCCCC2)CCCCC1.CN(C)C=O>C(OCC)(=O)C.O.C(O)(=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:3]2[C:2](/[CH:40]=[CH:39]/[C@H:27]3[O:26][C:25]([CH3:24])([CH3:41])[O:30][C@@H:29]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28]3)=[C:7]([CH:8]([CH3:10])[CH3:9])[N:6]=[C:5]([N:11]([CH3:16])[S:12]([CH3:15])(=[O:14])=[O:13])[N:4]=2)=[CH:18][CH:19]=1
Reactant: C=C[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1Br
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
A mixture of N-(5-bromo-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (1.00 g, 2.50 mmol), bis-tri-tert-butylphosphine palladium (0) (131 mg, 0.250 mmol), tert-butyl 2-((4R,6S)-2,2-dimethyl-6-vinyl-1,3-dioxan-4-yl)acetate (640 mg, 2.50 mmol), water (5 mL), N,N-dicyclohexylmethylamine (0.530 mL, 2.50 mmol), and N,N-dimethylformamide (5 mL) was heated and stirred at 50° C. under nitrogen for four days. The mixture was then diluted with ethyl acetate (11 mL), water (10 mL), and acetic acid (0.2 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (5 mL). The combined organic phases were washed with water (10 mL), then brine (10 mL), and concentrated in vacuo to give a yellow oil containing some solids. This material was adsorbed onto silica gel through dissolution in ethyl acetate, then purified by flash chromatography (5% ethyl acetate in isohexane gradually increasing to 20% ethyl acetate in hexane, silica column 25 mm in diameter and 250 mm in height) to yield tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethanesulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of the formula
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([C:43](Cl)=O)[CH:41]=[CH:42][C:35]1=2>>[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([CH2:43][C:4]3[C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[Br:1])[N:6]([C@@H:11]4[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]4[OH:13])[CH:5]=3)[CH:41]=[CH:42][C:35]1=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc2occc2c1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc4occc4c3)c3c(Br)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The titled compound was prepared from 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 22-(1) and benzo[b]furan-5-carbonyl chloride in a manner similar to Example 27 as a colorless powder. APCI-Mass m/Z 488/490 (M+H). 1H-NMR (DMSO-d6) δ 3.23 (td, J=9.1, 5.5 Hz, 1H), 3.37-3.47 (m, 3H), 3.61-3.69 (m, 2H), 4.39 (s, 2H), 4.53 (t, J=5.5 Hz, 1H), 5.09 (d, J=5.3 Hz, 1H), 5.15 (d, J=5.0 Hz, 1H), 5.22 (d, J=5.9 Hz, 1H), 5.40 (d, J=9.2 Hz, 1H), 6.87 (d, J=1.4 Hz, 1H), 7.04 (t, J=7.9 Hz, 1H), 7.21 (m, 2H), 7.25 (s, 1H), 7.43 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.93 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[NH:13]1.[CH:21]1([CH2:27]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:17][CH2:18][CH2:19][CH2:20]2)[N:13]1[CH2:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrCC1CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1CC1CCCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexylmethyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-(cyclohexylmethyl)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].C(OC([NH:11][C:12]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:21]([O:23][CH3:24])=[O:22])=O)(C)C>C1(C)C=CC=CC=1>[NH2:11][C:12]1[CH:20]=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1c(NC(=O)OC(C)C)ccc2c1CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)c1c(N)ccc2c1CCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Aluminium trichloride (146 mg, 1.09 mmol) was added to dry toluene (2 mL) at 0° C. Methyl 5-[(isopropoxycarbonyl)amino]indane-4-carboxylate (76 mg, 0.274 mmol) was added portionwise as a powder to the mixture above. The thick suspension was stirred at room temperature for 15 min and heated at 80° C. for 6 h. The mixture was poured into ice water and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford methyl 5-aminoindane-4-carboxylate. LCMS calc.=192.1; found=192.2 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.14 (d, J=8.1 Hz, 1H); 6.55 (d, J=8.1 Hz, 1H); 3.88 (s, 3H); 3.17 (t, J=7.5 Hz, 2H); 2.82 (t, J=7.5 Hz, 2H); 2.05-1.98 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.N1CCCC1>C(O)C>[CH3:10][N:11]1[CH2:12][CH:13]=[C:14]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[N:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:15][CH2:16]1
Reactant: CN1CCC(=O)CC1
Reactant: c1cc2[nH]ccc2cn1
Solvent: C1CCNC1
Solvent: CCO
Product: CN1CC=C(c2c[nH]c3ccncc23)CC1

Procedure:
from 5-azaindole (2.0 g, 16.9 mmol); N-methyl-4-piperidone (1.92 g, 16.9 mmol) and pyrrolidine (12.04 g, 169 mmol) in ethanol (20 mL).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1.[Cl:25][C:26]1[C:27]([CH3:38])=[C:28](I)[C:29]([O:35][CH3:36])=[C:30]([C:32](=[O:34])[CH3:33])[CH:31]=1>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:32]([C:30]1[C:29]([O:35][CH3:36])=[C:28]([CH:11]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:12]2)[C:27]([CH3:38])=[C:26]([Cl:25])[CH:31]=1)(=[O:34])[CH3:33]
Reactant: O=C(OCc1ccccc1)N1CC(I)C1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1I
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: BrCCBr
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Zinc (1.15 g, 17.6 mmol) was suspended with 1,2-dibromoethane (0.101 mL, 1.17 mmol) in DMF (21 mL). The mixture was heated at 70° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.149 mL, 1.17 mmol) was added dropwise and stirring was continued for 1 hour. A solution of benzyl 3-iodoazetidine-1-carboxylate (4.6 g, 15 mmol, from Pharmablock) in DMF (20 mL) was then added and the mixture was heated at 40° C. for 1 h before a mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (5.0 g, 15 mmol, from Example 60, Step 2), tris(dibenzylideneacetone)dipalladium(0) (0.27 g, 0.29 mmol) and tri-(2-furyl)phosphine (0.14 g, 0.59 mmol) in DMF (40 mL) was added. The reaction mixture was warmed to 70° C. and stirred overnight. The mixture was then cooled to room temperature and partitioned between ether and sat. NH4Cl solution. The organic layer was washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 20% EtOAc in hexane) to give the desired product (2.5 g, 44%). LCMS calculated for C21H23ClNO4 (M+H)+: m/z=338.1. found: 388.1.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[C:9]([CH3:21])=[C:10]([CH3:20])[C:11]([CH:18]=O)=[C:12]([CH:17]=2)[C:13](OC)=[O:14])=[CH:5][C:4]=1[F:24])#[N:2].[NH2:25][C@@H:26]1[C@@H:31]([OH:32])[CH2:30][CH2:29][O:28][CH2:27]1>C1COCC1>[C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[CH:17]=[C:12]3[C:11]([CH2:18][N:25]([C@@H:26]4[C@@H:31]([OH:32])[CH2:30][CH2:29][O:28][CH2:27]4)[C:13]3=[O:14])=[C:10]([CH3:20])[C:9]=2[CH3:21])=[CH:5][C:4]=1[F:24])#[N:2]
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(C#N)c(F)c2)c(C)c(C)c1C=O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(C#N)c(F)c2)cc2c(c1C)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
To a solution of methyl 5-(4-cyano-3-fluorobenzyl)-2-formyl-3,4-dimethylbenzoate (0.25 g) in THF (5.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.09 g), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction mixture was concentrated, and the residue was diluted with acetic acid (5.00 mL). Then, sodium triacetoxyborohydride (0.24 g) was added thereto and the mixture was stirred at room temperature for 2 hr under argon atmosphere. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane, methanol/ethyl acetate) to give the title compound (0.16 g).
Reaction SMILES: [C:1]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>C1(C)C=CC=CC=1>[Cl:10][C:9]1[C:4]([C:1](=[O:3])[CH:2]=[C:17]([N:19]([CH3:21])[CH3:20])[CH3:18])=[N:5][CH:6]=[C:7]([C:11]([F:13])([F:14])[F:12])[CH:8]=1
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Product: CC(=CC(=O)c1ncc(C(F)(F)F)cc1Cl)N(C)C
Yield: 66.4 %

Procedure:
1.0 g of 2-acetyl-3-chloro-5-(trifluoromethyl)pyridine and 715 mg of N,N-dimethylacetamide dimethyl acetal were reacted in 6 mL of toluene at 100° C. for 14 hours. The reaction liquid was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 869 mg of 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-3-(dimethylamino)-2-buten-1-one (after-mentioned intermediate No. IV-1).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1.Br[CH2:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:15][CH2:16][O:17][CH3:18])[CH2:6]1
Reactant: Brc1ccccc1OC1CCNC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1CCC(Oc2ccccc2Br)C1
Reaction time: 48 h

Procedure:
3-(2-Bromophenoxy)pyrrolidine (1.23 g), 1-bromo-2-methoxyethane (0.526 ml) and potassium carbonate (842 mg) were mixed with dimethylformamide (50 ml) and stirred for two days. The mixture was added to water (100 ml). The mixture was extracted with diethyl ether (3×50 ml), washed with water (2×50 ml), brine (2×30 ml), dried (MgSO4) and concentrated in vacuo. Purification was achieved using cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures yielding product as a clear oil (0.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]([CH3:17])([CH3:16])[C:14]#[CH:15].N12CCCN=C1CCCCC2.O>C(#N)C.[Cu](Cl)Cl>[CH3:16][C:13]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])([CH3:17])[C:14]#[CH:15]
Reactant: COC(=O)c1cccc(O)c1
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: C#CC(C)(C)Oc1cccc(C(=O)OC)c1
Reaction time: 0.25 h
Yield: 27.9 %

Procedure:
To a solution of methyl 3-hydroxybenzoate (10.0 g, 65.7 mmol) in acetonitrile (200 mL) were added 3-chloro-3-methylbut-1-yne (20.0 g, 195 mmol) and copper (II) chloride (88 mg, 0.654 mmol) under ice-cooling, and the mixture was stirred for 15 min under ice-cooling. 1,8-Diazabicyclo[5.4.0]undec-7-ene (10 mL, 70.0 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water (300 mL), and the mixture was extracted with ethyl acetate (400 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→0/100) to give the title compound (4.0 g, 28%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[C:12]([C:35]3[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H](CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O)O[Si](C)(C)C(C)(C)C
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CSc1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, a mixture of the product from Example 545C (0.98 g, 2 mmol), 4-(methylthio)benzeneboronic acid (0.4 g, 2.4 mmol), K3PO4 (1.2 g, 6 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol), isopropanol (9 mL), and water (1 mL) was stirred at 70° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (30 mL) was added and stirring was continued for 2 hours. The crude black precipitate was collected by filtration then Washed with water (10 mL) and hexane (10 mL). This title intermediate was used without further purification in the following oxidation/deprotection step.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([F:23])[CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].ClC(Cl)C.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:17]([F:23])[CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(-c3ccc(C=O)c(F)c3)n2n1
Reactant: CC(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCNc1ccc2ncc(-c3ccc(CNC(C)(C)C)c(F)c3)n2n1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-2-fluoro-benzaldehyde (30 mg, 0.10 mmol) and dichloroethane (DCE, 1 mL) was treated with tert-butyl amine (0.011 mL, 0.11 mmol) and the resulting reaction mixture was maintained at RT for 20 min. The reaction was then treated with sodium triacetoxyborohydride (23 mg, 0.11 mmol) and the resulting mixture was maintained until LCMS indicated complete consumption of the aldehyde. The reaction was quenched with saturated aqueous sodium bicarbonate, the layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by reverse phase HPLC to afford butyl-{3-[4-(tert-butylamino-methyl)-3-fluoro-phenyl]-imidazo[1,2-b]pyridazin-6-yl}-amine (32 mg, 86%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.21 (dd, J=12.3, 1.5 Hz, 1H), 7.93 (dd, J=8.0, 1.7 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=9.7 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 6.68 (d, J=9.7 Hz, 1H), 4.02 (s, 2H), 3.34 (t, J=7.2 Hz, 2H), 1.60-1.73 (m, 2H), 1.39-1.51 (m, 2H), 1.24-1.35 (m, 10H), 0.91-1.00 (m, 3H); LCMS (ESI) m/e 370.2 [(M+H)+, calcd for C21H29FN5 370.2].
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Cl[CH2:12][C:13]([NH:15][C:16]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)=[O:14]>C(O)C>[N+:30]([C:27]1[CH:28]=[CH:29][C:16]2[NH:15][C:13](=[O:14])[CH2:12][N:2]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]=2[CH:26]=1)([O-:32])=[O:31]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 2-liter, 4-necked flask equipped with a stirrer, a reflux condenser and an ammonia tube, there was added 600 ml. of ethanol and 37.9 g. of hexamethylenetetramine with stirring. Ammonia was bubbled through the resultant reaction medium with stirring until reflux temperature was reached. Then there was carefully added to the refluxing solution 40.0 g. of 2-chloroacetamido-5-nitro benzophenone. Ammonia is steadily bubbled into the reaction mixture while continuing to reflux for three hours. The resultant solution was cooled, evaporated to dryness at 50° C. The residue was dissolved in 300 ml. of toluene. 0.3 G. of paratoluene sulfonic acid was added to the resultant solution. The solution was heated to reflux. The refluxing was continued for 1 hour. The reaction medium was then permitted to cool to room temperature. The product which separated was filtered off, washed with water and dried. This material was taken up in 435 ml. of methylene chloride. It was then filtered through Hyflo. Upon the addition of 90 ml. of 3N nitric acid to the filtrate, crystals appeared. They were filtered off, washed with methylenechloride and dried for 15 minutes. The crystals were added to 1 liter of water with stirring. Ammonium hydroxide was then carefully added to the resultant medium until a pH of about 8 was reached. After stirring the resultant medium for 1/2 hours, the crystalline precipitate which formed were filtered off, washed with cold water and dried at 80° for 8 hours yielding 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one of melting point 217°-219° .
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH2:19])[CH2:4][CH3:5])[CH3:2].[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[CH2:1]([N:3]([CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:19][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([CH3:20])=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CCn1c(N)nc2ccc(OC)cc21
Product: CCN(CC)CCn1c(NC(=O)c2ccc(C)cc2)nc2ccc(OC)cc21

Procedure:
1-(N,N-Diethylaminoethyl)-2-(4-methylbenzamido)-6-methoxybenzimidazole was prepared by the method of Example 2 using 1-(N,N-diethylaminoethyl)-2-amino-6-methoxybenzimidazole and 4-methylbenzoyl chloride. 1H NMR (DMSO): δ 1.33(t, 6H), 2.51 (s, CH3 ar), 3.40 (m, 4H), 3.58 (m, 2H), 3.98 (s, 3H), 4.87 (m 2H), 6.99-8.28 (4 m, 7 H), 11.61 (broad s, NH).
Reaction SMILES: [CH3:1][Mg]Br.[F:4][C:5]([F:26])([F:25])[C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH:15]=[O:16])[CH:14]=1)[N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[CH:9]2>O1CCCC1>[F:26][C:5]([F:4])([F:25])[C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH:15]([OH:16])[CH3:1])[CH:14]=1)[N:11]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[CH:10]=[CH:9]2
Reactant: C[Mg]Br
Reactant: C[Si](C)(C)CCOCn1ccc2cc(C(F)(F)F)cc(C=O)c21
Solvent: C1CCOC1
Product: CC(O)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (0.582 ml, 1.747 mmol) was added dropwise to a 0° C. solution of 5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-7-carbaldehyde (500 mg, 1.456 mmol) in tetrahydrofuran (10 ml). The reaction was stirred 30 min at 0° C. An additional portion of methylmagnesium bromide (0.58 ml, 1.75 mmol) was added. The reaction was stirred another 30 min, quenched by addition of water (10 mL), and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of 5% to 40% ethyl acetate/hexanes to give 427 mg (82%) as a yellow liquid. 1H-NMR (CDCl3, 400 MHz) δ 7.84 (d, J=1.1 Hz, 1H), 7.62 (d, J=1.0 Hz, 1H), 7.18 (d, J=3.2 Hz, 1H), 6.59 (d, J=3.3 Hz, 1H), 5.74 (d, J=11.5 Hz, 1H), 5.68 (m, 1H), 5.59 (d, J=11.4 Hz, 1H), 3.44 (dd, J=8.4, 7.8 Hz, 2H), 1.69 (d, J=6.3 Hz, 3H), 0.87 (m, 2H), −0.10 (s, 9H); LC/MS (HPLC method 4): tR=3.743 min, 382.12(MH)+.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)=[C:2]=[S:3].[OH:10][CH2:11][CH:12]1[NH:17][CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1.C(O)(C)C.C(OC(C)C)(C)C>C(O)C>[OH:10][CH2:11][CH:12]1[N:17]([C:2](=[S:3])[NH:1][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][C:15]2[S:18][CH:19]=[CH:20][C:14]=2[CH2:13]1
Reactant: OCC1Cc2ccsc2CN1
Reactant: S=C=Nc1cccnc1
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: OCC1Cc2ccsc2CN1C(=S)Nc1cccnc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A solution of 3-isothiocyanatopyridine (1.36 g) in absolute ethanol (40 cc) is added dropwise, at a temperature of about 0° C., to a solution of (RS)-5-hydroxymethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1.69 g) in absolute ethanol (60 cc). The resulting solution is stirred for 20 hours at a temperature of about 20° C. and the solid formed is then filtered off. The filtrate is evaporated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. and a white solid is obtained which is combined with the solid isolated by filtration. These solids are dissolved in a mixture, heated under reflux, of isopropanol and diisopropyl ether (1:2 by volume; 150 cc) and the solution, after cooling, is kept at +5° C. for 20 hours. The resulting crystals are filtered off, washed with diisopropyl ether (50 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)-5-Hydroxymethyl-6-[(pyrid-3-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2.3 g) is thus obtained in the form of white crystals melting at 165° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH3:31])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[CH3:28]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CCNCC
Product: CCN(CC)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and diethylamine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 450.4 (MH+).