Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Ic1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine 634 (2.00 g, 8.20 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (60% dispersion in mineral oil, 390 mg, 9.8 mmol) was added. After 20 minutes, triisopropylsilyl chloride (1.74 mL, 8.20 mmol) was added dropwise. After 1.5 hours, the reaction was poured into water and extracted with ethyl acetate, washed with saturated sodium bicarbonate and brine. The organic portions were dried over anhydrous sodium sulfate and concentrated. Purification by silica gel chromatography, 0-25% gradient ethyl acetate/hexane gave compound 635 as a white solid (3.224 g, 98.2%). 1H-NMR was consistent with the desired compound.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[CH:13](OCC)(OCC)OCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[O:12]1[C:11]2=[CH:10][CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]2[N:2]=[CH:13]1
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: CCOC(OCC)OCC
Agent: Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: O=C(O)c1cccc2ocnc12
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A mixture of 2-amino-3-hydroxybenzoic acid hydrobromide (300 mg, 1.28 mmol), triethyl orthoformate (0.85 mL, 5.1 mmol), pyridinium p-toluenesulfonate (64 mg, 0.26 mmol) and xylenes (15 mL) was refluxed for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford the benzoxazole-4-carboxylic acid (210 mg, quantitative) as a light yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 13.12 (s, 1H), 8.86 (s, 1H), 8.03 (dd, J=8.1, 0.9 Hz, 1H), 7.92 (dd, J=8.1, 0.9 Hz, 1H), 7.54 (t, J=8.1 Hz, 1H); MS (ESI+) m/z 164 (M+H).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[NH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH3:40])=[C:37]([OH:39])[CH:38]=1>C1COCC1>[OH:39][C:37]1[CH:38]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:31])[CH:34]=[CH:35][C:36]=1[CH3:40]
Reactant: Cc1ccc(N)cc1O
Reactant: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 27.1 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 69, 100 mg, 0.240 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (32.5, 0.264 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 27% (34 g, 0.065 mmol) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]2SCCS2)[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2].O.S(Cl)(Cl)(=O)=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[CH:23]=[O:33])[N:9]([CH3:28])[CH2:8]1)=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C5SCCS5)c(c34)C[C@H]2N(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C=O)c(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
2.05 g (5 mmol) of 1,1-diethyl-3-[2-(1,3-dithiolan-2-yl)-6-methyl-8α-ergolinyl]urea is dissolved under argon in 46 ml of chloroform. Then 3.5 g of silica gel and, under vigorous agitation, dropwise 3.5 ml of water are added. During a time period of 30 minutes, a solution of 1.18 ml of sulfuryl chloride in 30 ml of chloroform is added drop by drop. After stirring for 3 hours at room temperature, 7.5 g of potassium carbonate is added and the mixture is vigorously stirred for 20 minutes. The precipitate is filtered off and washed with chloroform. The precipitate is moistened with ethanol and introduced into 300 ml of saturated sodium chloride solution which is then repeatedly extracted with chloroform. The chloroform extracts and the chloroform filtrate are jointly dried over magnesium sulfate and evaporated. The subsequent crystallization is performed from ethyl acetate, thus isolating 0.93 g of 1,1-diethyl-3-(6-methyl-2-formyl-8α-ergolinyl)urea (54% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1.O.Cl.[NH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>C(Cl)(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][C:12]2[S:16][C:15]([S:17]([N:23]3[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]3)(=[O:19])=[O:18])=[CH:14][CH:13]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCN(S(=O)(=O)c2ccc(CNC(=O)c3ccc(Cl)cc3)s2)CC1

Procedure:
A solution of 5-({[1-(4-Chloro-phenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonyl chloride (1b) (5.0 g, 14 mmol) in 100 ml chloroform and a solution of 4-piperidinone hydrochloride monohydrate (4.3 g, 28 mmol) in 21 ml of NaOH (2N) were stirred vigorously for 15 h. The reaction was quenched with HCl (2N) and the organic layer was extracted twice with HCl (2N) and twice with brine. The dried organic phase affords after evaporation of chloroform 5.8 g (99.5%) of (63c) as a colourless solid: 1H NMR (CDCl3) δ7.67 (d, J=8.7 Hz, 2H), 7.42-7.38 (m, 3H), 6.99 (d, J=3.8 Hz, 1H), 6.53 (t, J=5.3 Hz, 1H), 4.74 (d, J=6.0 Hz, 2H), 3.37 (d, J=6.2 Hz, 4H), 2.50 (d, H=6.2 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12](OS(C(F)(F)F)(=O)=O)[C:11]=1[N+:24]([O-:26])=[O:25].Cl.[CH3:28][O:29][CH2:30][CH:31]([NH2:33])[CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:33][CH:31]([CH3:32])[CH2:30][O:29][CH3:28])[C:11]=1[N+:24]([O-:26])=[O:25]
Reactant: COCC(C)N
Reactant: COc1ccc(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])c(Cl)c1
Agent: Cl
Product: COCC(C)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Yield: 34.1 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl ester (1.0 g, 2.42 mmol), prepared substantially as described in Part C of Example 19a, and 2-methoxy-1-methyl-ethylamine HCl (0.61 g, 4.85 mmol) were treated substantially as described in Part C of Example 19a to produce 0.29 g (34%) of [4-(2-chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(2-methoxy-1-methyl-ethyl)-amine: MS (AP) m/z 351.8 [(M+H)+, 100].
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:20][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: c1ccc(CN2CCCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(CN2CCCN(CCC(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
The resulting benzyihomopiperazine was dissolved in 3 mL of ethanol, to which were added 296 mg of 3,3-diphenylpropyl methanesulfonate and 136 mg of potassium carbonate. The mixture was stirred at 70° C. for 15 hours and it was cooled to room temperature and the solvent was removed under reduced pressure. 20 mL of aqueous 2N sodium hydroxide was added and the solution was extracted with 20 mL×2 of ethyl acetate. The organic layers were combined and washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by column chromatography (silica gel, ethyl acetate) to obtain 135 mg of the titled compound. This was treated with a hydrogen chloride solution in ether followed by removing the solvent under reduced pressure and drying to give the hydrochloride salt of the titled compound.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([C:22](=[O:24])[CH3:23])[CH3:21]>CN(C)C=O.C(OCC)(=O)C>[CH3:21][CH:20]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)[CH:1]=[O:2])[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)C(C)Br
Reactant: O=CNc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)C(C)N(C=O)c1cccc([N+](=O)[O-])c1
Reaction time: 72 h
Yield: 99.9 %

Procedure:
To a suspension of N-formyl-3-nitroaniline (831 mg) and potassium carbonate (830 mg) in N,N-dimethylformamide (5 ml) was added 2-bromo-3-butanone (906 mg), and the mixture was stirred for 72 hours. The mixture was diluted with ethyl acetate and washed with water and brine. The mixture was dried over magnesium sulfate and evaporated to give N-(1-methyl-2-oxo-propyl)-N-(3-nitrophenyl)formamide (1.18 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH:22]([CH3:24])[CH3:23])=[CH:17][CH2:16][C:15]([CH3:26])([CH3:25])[C:14]=3[CH:13]=2)=[CH:7][CH:6]=1)[CH3:2].[CH:28](=O)[CH3:29]>>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:28][CH3:29])[C:12]2[CH:21]=[CH:20][C:19]3[C:18]([CH:22]([CH3:23])[CH3:24])=[CH:17][CH2:16][C:15]([CH3:25])([CH3:26])[C:14]=3[CH:13]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CC=O
Reactant: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3C(C)C)cc1
Product: CCOC(=O)c1ccc(N(CC)c2ccc3c(c2)C(C)(C)CC=C3C(C)C)cc1

Procedure:
Following General Procedure M, 4-(5-isopropyl-8,8-dimethyl-7,8-dihydro-naphthalen-2-ylamino)-benzoic acid ethyl ester (Compound 79, 10 mg, 0.06 mmol), was reacted with acetaldehyde to give the title compound as a yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]1[C:17]([Cl:18])=[N:16][C:15](Cl)=[CH:14][N:13]=1)=[O:11].[CH3:20][O:21][C:22](=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]>CN(C=O)C>[CH3:20][O:21][C:22](=[O:31])[CH:23]([C:15]1[CH:14]=[N:13][C:12]([C:10](=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])=[C:17]([Cl:18])[N:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30]
Reactant: O=C(c1ccccc1Cl)c1ncc(Cl)nc1Cl
Reactant: COC(=O)Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1cnc(C(=O)c2ccccc2Cl)c(Cl)n1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of sodium hydride (0.175 g, 7 mmol) and (2-Chloro-phenyl)-(3,5-dichloro-pyrazin-2-yl)-methanone (0.86 g, 2.99 mmol) in 5 mL DMF was added (2-Fluoro-phenyl)-acetic acid methyl ester (0.503 g, 2.99 mmol). The reaction mixture was stirred for one hour at room temperature, and then was quenched by addition of water and aqueous HCl. The aqueous mixture was extracted with methylene chloride, and the combined organic phases were dried over MgSO4, filtered, and evaporated under reduced pressure to give 1.19 g of crude [6-Chloro-5-(2-chloro-benzoyl)-pyrazin-2-yl]-(2-fluoro-phenyl)-acetic acid methyl ester. Mass Spec. M+H=419.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=1>CN1CCCC1=O.O>[F:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH2:20][CH2:19][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[C:5]2[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:6]1=2
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: COc1ccc(CCBr)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 4632.5 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 0.0022 mmol) was dissolved in N-methyl 2-pyrolidone (4.0 mL). Powdered potassium hydroxide (1 g, 0.008 mol) was added and heated at 100° C. for 2 h. 4-(2-Bromo-ethyl)-2-fluoro-1-methoxy-benzene (0.520 g, 0.0022 mol) was added at the room temperature and stir for 0.5 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.038 g, 4% yield). 8-Chloro-5-[2-(3-fluoro-4-methoxy-phenyl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0038 g, 0.00010 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.00010 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.016 g, 34% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[C:7]2[OH:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18]>CN1CCCC1=O>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:9]2[N:8]=[C:7]([OH:13])[C:6]3[C:11](=[C:2]([Br:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Oc1nc(Cl)nc2c(Br)cccc12
Solvent: CN1CCCC1=O
Product: Oc1nc(Nc2ccc(Cl)c(Cl)c2)nc2c(Br)cccc12
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A solution of 8-bromo-2-chloroquinazolin-4-ol (0.37 g) and 3,4-dichloroaniline (0.69 g) in 1-methyl-2-pyrrolidinone (8 mL) was heated at 140° C. for 3 h. The mixture was then cooled to room temperature and poured onto ice/water (100 mL). The precipitate which formed was isolated by filtration, washed sequentially with water and diethyl ether, then was dried in vacuo to afford the title compound (0.46 g). 1H NMR (300 MHz, DMSO-d6): δ11.14 (s, 1H), 9.22 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.57-7.51 (m, 2H), 7.20-7.18 (m, 1H). HPLC Method B: 9.90 min. MS (APCI+): m/z 386, 388. (APCI−): m/z 384, 386. The starting material 8-Bromo-2-chloroquinazolin-4-ol was prepared as follows:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]=1.[CH3:17]I.[BH4-].[Na+]>CCOC(C)=O>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:16])[O:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH3:17]
Reactant: COC(=O)Nc1ccc2c(c1)CCN=C2C
Reactant: CI
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc2c(c1)CCN(C)C2C
Reaction time: 72 h

Procedure:
A mixture of 1.00 g (4.5 mmol) methyl (1-methyl-3,4-dihydro-isoquinolin-6-yl)-carbamate, 2.3 ml (37 mmol) methyl iodide and 25 ml EtOAc is stirred for 72 h. The crystals precipitated are filtered off, taken up in 10 ml of methanol and 140 mg (3.6 mmol) sodium borohydride are added batchwise. After 2 h the mixture is concentrated and purified by chromatography (silica gel; dichloromethane/methanol 90:10).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][C@@H:27]([CH3:30])[CH2:28][OH:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: C[C@H](N)CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H](C)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 8-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)-2-aminopropan-1-ol. MS obsd. (ESI+) [(M+H)+] 412, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (t, J=6.32 Hz, 2 H), 7.75 (s, 1 H), 7.64 (t, J=7.20 Hz, 1 H), 7.55-7.43 (m, 1 H), 7.38-7.27 (m, 1 H), 7.27-7.14 (m, 1 H), 6.16 (d, J=8.08 Hz, 1 H), 6.07 (s, 1 H), 5.07 (brs, 2 H), 4.85 (brs, 1 H), 4.42 (brs, 1 H), 3.85 (dt, J=12.82, 6.35 Hz, 1 H), 3.70-3.47 (m, 3 H), 2.36 (s, 3 H), 1.23 (d, J=6.32 Hz, 3 H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:32][NH2:33]>O1CCCC1>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nn2)CC1

Procedure:
The procedure described in Example 1 (step 1.4.) is used. Starting with 0.66 g (1.51 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{6-[3-(trifluoromethyl)phenyl]-3-pyridazinyl}-1-piperazinecarboxylate, obtained in step 10.2, and 3 ml (6.02 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 96/4 mixture of dichloromethane and methanol, followed by washing with diisopropyl ether, 0.50 g of product is obtained in the form of a white solid.
Reaction SMILES: I[C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][C:3]=1[CH3:20].CO.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.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>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[NH:6][C:5]([C@@H:7]4[CH2:11][C@H:10]([CH3:12])[CH2:9][N:8]4[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:4][C:3]=3[CH3:20])=[CH:32][CH:31]=2)=[CH:28][CH:29]=1
Reactant: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1nc([C@@H]2C[C@H](C)CN2C(=O)OC(C)(C)C)[nH]c1-c1ccc(-c2ccc(Br)cc2)cc1
Temperature: 75 °C
Yield: 43.6 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(5-iodo-4-methyl-1H-imidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (289 mg, 0.7387 mmol) in 6 mL of 5:1 toluene:methanol is sequentially added [4-(4-bromophenyl)phenyl]boronic acid (346.7 mg, 1.252 mmol), K3PO4 (199.3 mg, 0.9389 mmol) and Pd(PPh3)4 (71.85 mg, 0.06218 mmol). The reaction mixture is heated at 75° C. for 3 hours. The reaction mixture is concentrated, diluted with ethyl acetate, and washed with water and brine. The organic layer is concentrated to dryness. The residue is dissolved in dichloromethane and purified by flash column chromatography on silica gel (0-10% methanol/dichloromethane) to give (2S,4S)-tert-butyl 2-(5-(4′-bromo-[1,1′-biphenyl]-4-yl)-4-methyl-1H-imidazol-2-yl)-4-methylpyrrolidine-1-carboxylate (160 mg, 0.322 mmol).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:5][C:6]1[N:10]([S:11]([C:14]2[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:9]=[N:8][CH:7]=1)=[O:4].[BH4-].[Na+].Cl>CO>[F:1][CH2:2][CH:3]([OH:4])[CH2:5][C:6]1[N:10]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=2)(=[O:13])=[O:12])[CH:9]=[N:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cncc2CC(=O)CF)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cncc2CC(O)CF)cc1

Procedure:
A solution of 20 mmole of 1-tosyl-5-imidazolylmethyl fluoromethyl ketone in 25 ml of methanol cooled to -10° C. is treated with 30 mg of sodium borohydride. After two hours at from -10° to 0° C. the reaction mixture is neutralized with 6 M HCl and concentrated under vacuo. The residue is extracted several times with chloroform. Evaporation of the solvent affords an oil which is purified by distillation under high vacuum to give 3-fluoro-1-(1-tosyl-5-imidazolyl)propan-2-ol. A solution of 2 g of 3-fluoro-1-(1-tosyl-5-imidazolyl)propan-2-ol, 1.37 g of phthalimide, 1.74 g of diethylazodicarboxylate in 2.4 g of triphenylphosphine and 25 ml of tetrahydrofuran is stirred under nitrogen at 25° C. for 20 hours after which the solvent is evaporated at reduced pressure and the residue is taken up in benzene. The insoluble material is discarded and the semi-solid residue obtained after concentration of the filtrate under vacuum is recrystallized using dichloromethane/diethylether to give the fluorophthalimide derivative. A solution of 1.12 g of the fluorophthalimide derivative in 0.18 g of hydrazine hydrate in 42 ml of absolute ethanol is heated at reflux for 5 hours. Upon cooling the solution is concentrated under vacuum to a volume of 15 ml, allowed to stand overnight at 0° C. then filtered. The filtrate is concentrated and distilled under high vacuum to afford 1-fluoromethyl-2-(1-tosyl-5-imidazolyl)ethylamine which is combined with 6 ml of 47% hydrogen bromide and heated under nitrogen at 100° C. for 4 hours then concentrated under reduced pressure to give a solid residue. The residue is recrystallized from ethanol-diethylether to give 1-fluoromethyl-2-(5-imidazolyl)ethylamine hydrobromide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:19])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CO
Reactant: COC(=O)c1ccc(C(=O)O)cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)OC)c(Br)c1
Yield: 98 %

Procedure:
To a solution of 3-bromo-4-(methoxycarbonyl)benzoic acid (3.0 g, 11.6 mmol) in MeOH (50 mL) was slowly added SOCl2 (2.76 g, 23.2 mmol) dropwise. After the addition completion, the reaction mixture was refluxed for 5 h. Then MeOH was removed and water was added. It was extracted with EA and the organic layer was washed with aqueous sodium bicarbonate solution, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give dimethyl 2-bromoterephthalate (3.1 g, yield 98%) as a white solid. It was used without further purification in the next step.