Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:17]3[O:21][CH:20]=[CH:19][CH:18]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=Cc1ccco1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Clc1cc(Cl)cc(Nc2n[nH]c(NCc3ccco3)n2)c1
Reaction time: 1 h
Yield: 54 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and furfural (85.1 mg, 886 μmol) in MeOH (3 ml) was stirred at room temperature for 3 days. The resulting suspension was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (65.1 mg, 1.72 mmol) was added and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in DCM and washed with water (2×4 ml), dried over MgSO4 and concentrated to give a solid. Trituration with DCM/Hexanes afforded a white solid as desired product (50.5 mg, 54% yield). MS +m/z: 324 (M+H)+
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 21 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)-amide-hydrochloride and n-heptyl chloroformate. Yield: 21% of theory, C34H41N7O5 (627.8) Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1) ##EQU77##
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:27])[CH2:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>CO.CCOC(C)=O>[CH3:26][O:25][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:12]([N:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:11][CH2:10]2)=[O:27])[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[O:23][CH3:24]
Reactant: CCOC(=O)CN1CCN(C(=O)CCc2cc(OC)c(OC)c(OC)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(CCC(=O)N2CCN(CC(=O)O)CC2)cc(OC)c1OC
Reaction time: 1 h
Yield: 96.1 %

Procedure:
Dissolve {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid ethyl ester (45) (100 mg, 0.25 mmol) in MeOH (2.0 mL) at rt and add 2M aqu NaOH (260 μL, 0.52 mmol). Stir the reaction mixture for 1 h under reflux. Add dropwise 1M aqu. HCl (550 μL, 0.55 mmol), extract the mixture with EtOAc (3 times) and remove solvent obtain {4-[3-(3,4,5-Trimethoxy-phenyl)-propionyl]-piperazin-1-yl}-acetic acid (46) (88 mg, 95%) as a brown sticky solid. No further purification. 1H NMR (400 MHz, CDCl3/CD3OD 9+1): 2.54 (br.t, 2H); 2.78 (t, 2H, J=7.5 Hz); 2.83-3.10 (br.m, 2H); 3.24 (s, 2H); 3.43-3.62 (br.m, 2H); 3.68 (s, 3H); 3.73 (s, 6H); 3.74-3.85 (br.m, 4H); 6.34 (s, 2H).
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:19][CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24].[C:27]1([O-:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Na+]>C1COCC1>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[O:33]([CH2:19][CH2:20][CH2:21][CH2:22][S:23]([O-:26])(=[O:25])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [O-]c1ccccc1
Reactant: O=S(=O)([O-])CCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)([O-])CCCCOc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of tetrabutylammonium-4-chlorobutylsulfonate in THF a solution of sodium phenolate in THF is added dropwise under cooling. After complete addition, the solution is allowed to warm to room temperature. The precipitate is filtered off and the remaining solution is concentrated with a rotary evaporator to yield tetrabutylammonium-4-phenoxybutylsulfonate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].[N+:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)([O-:14])=[O:13].[CH3:22]S(C)=O>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([C:18]2[CH:19]=[CH:20][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][C:17]=2[CH3:22])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CS(C)=O
Reactant: CCOCCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCOCCN1CCN(c2ccc([N+](=O)[O-])cc2C)CC1

Procedure:
In the same manner as in Production Example 5-1, but using 4-(2-ethoxyethyl)piperazine in place of N-ethylpiperazine used in Production Example 5-1, using 4-nitrofluorobenzene in place of 2-fluoro-5-nitrobenzyl alcohol, and using dimethylsulfoxide in place of N-methylpyrrolidone, 1.50 g of the entitled compound was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:18]1[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=1[CH3:25]>>[CH3:1][C:2]1[O:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:18]3[S:22][C:21]([C:23]#[N:24])=[CH:20][C:19]=3[CH3:25])[CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: Cc1cc(C#N)sc1Br
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCC2)O1
Product: CC1=Nc2ccc(-c3sc(C#N)cc3C)cc2C2(CCCC2)O1

Procedure:
The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclopentane] and 5-bromo-4-methyl-2-thiophenecarbonitrile. A yellowish solid: mp 58-60° C.; 1H-NMR (DMSO-d6) δ 7.79 (s, 1H), 7.16 (d, 1H, J=1.9 Hz), 7.12 (dd, 1H, J=8.4, 2.2 Hz), 6.66 (s, 1H), 6.63 (d, 1H, J=8.4 Hz), 4.75 (m, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 6H), 1.32 (d, 3H, J=5.5 Hz).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([NH:14][CH3:15])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[S:38](Cl)(=[O:40])=[O:39].CC(O)=O>C(#N)C>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([N:14]([CH3:15])[S:38]([C:34]4[S:33][CH:37]=[CH:36][CH:35]=4)(=[O:40])=[O:39])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOc1ccc(Cc2nc3cc(NC)cnc3n2CC2CC2)cc1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccc(Cc2nc3cc(N(C)S(=O)(=O)c4cccs4)cnc3n2CC2CC2)cc1
Reaction time: 8 h
Yield: 18 %

Procedure:
To a solution of 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine (250.0 mg, 0.74 mmol) in acetonitrile (5 mL) at room temperature was added triethylamine (207 mL, 1.49 mmol) followed by 2-thiophenesulfonyl chloride (176 μL, 0.96 mmol). The mixture was stirred overnight. The reaction mixture was concentrated in vacuo. The residue was dissolved into EtOAc (10 ml) and Na2CO3 saturated aqueous solution (10 mL). The phases were separated and the aqueous phase was back-extracted with additional EtOAc (10 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified using preparative HPLC (C-18 column, 20 to 80% [0.1% AcOH in AcCN solution] in 0.1% AcOH aqueous solution) to provide 72 mg of the AcOH salt of the title compound N-[3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-3H-imidazo[4,5-b]pyridin-6-yl]-N-methyl-2-thiophenesulfonamide (18% yield from 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-N-methyl-3H-imidazo[4,5-b]pyridin-6-amine). 1H-NMR (400 MHz, d3-MeOD): δ 0.37 (m, 2H), 0.43 (m, 2H), 1.10 (m, 1H), 1.35 (t, J=7.0 Hz, 3H), 3.32 (s, 3H), 3.99 (t, J=7.0 Hz, 2H), 4.10 (d, J=7.2 Hz, 2H), 4.32 (s, 2H), 6.86 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.8 Hz, 2H), 7.20 (m, 1H), 7.44 (d, J=5.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.85 (d, J=5.1 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H). MS (ESI) (M+H)+: 483.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Mg].II.[C:12]([O:16][C:17](=[O:28])[N:18]([CH2:20][CH2:21][C:22](=[O:27])N(OC)C)[CH3:19])([CH3:15])([CH3:14])[CH3:13].CCOC(C1N=C(C2N3C(=NC(C4C=CC=CC=4)=N3)SC=2)SC=1)=O>O1CCCC1>[C:12]([O:16][C:17](=[O:28])[N:18]([CH2:20][CH2:21][C:22](=[O:27])[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:19])([CH3:15])([CH3:13])[CH3:14]
Reactant: CON(C)C(=O)CCN(C)C(=O)OC(C)(C)C
Reactant: BrCC1CCCCC1
Agent: CCOC(=O)c1csc(-c2csc3nc(-c4ccccc4)nn23)n1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CN(CCC(=O)CC1CCCCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
Add dropwise bromomethylcyclohexane (16.96 mL, 0.121 mol) to a stirred warm solution of magnesium (granulae, 3.02 g, 0.124 mol), a crystal of iodine and tetrahydrofuran (130 mL). Heat the mixture to reflux for one hour. Add the Grignard reagent (30 mL) to a stirred mixture of [2-(methoxy-methyl-carbamoyl)-ethyl]-methyl-carbamic acid tert-butyl ester (3.0 g, 12.0 mmol, prepared according to Blaney, P.; Grigg, R.; Rankovic, Z.; Thornton-Pett, M.; Xu, J. Tetrahedron 2002, 1719-1737) and tetrahydrofuran (120 mL) kept at 0° C. under N2. Stir the mixture for one h at 0° C. and for 2 h at room temperature. Add more of the Grignard reagent (40 mL) and stir for another hour at room temperature. Add saturated aqueous ammonium chloride and separated the layers. Extract the water layer with diethyl ether (×3). Dry the combined organic layers, filter and concentrate. Purify the crude residue by flash column chromatography, eluting with ethyl acetate/hexane (1:9) to yield 1.0 g of the title compound. 1H NMR (CDCl3) δ 3.46-3.40 (m, 2H), 2.85 (s, 3H), 2.68-2.60 (m, 2H), 2.29 (d, 2H), 1.87-1.60 (m, 6H), 1.46 (s, 9H), 1.33-1.07 (m, 3H), 0.99-0.86 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]([CH3:12])[C:8](=[S:11])[NH:9][N:10]=1.IC.Cl[CH2:16]Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH3:12][N:7]1[C:8]([S:11][CH3:16])=[N:9][N:10]=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: ClCCl
Reactant: Cn1c(CCCCO)n[nH]c1=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CSc1nnc(CCCCO)n1C

Procedure:
5-(4-hydroxybutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (1 g) was dissolved in ethanol (6 ml), Iodomethane (0.4 ml) was added dropwise and the reaction was refluxed for 1 h. Dichloromethane and NaHCO3 saturated solution were added. Solvent was removed under reduced to give a crude product that was purified by flash chromatography on silica gel (eluting with DCM/MeOH from 0 to 10%) to give the title compound (0.73 g).
Reaction SMILES: Cl[CH:2]([C:4]1[N:5]=CSC=1)[CH3:3].[C-:9]#[N:10].[Na+].[CH3:12][S:13]([CH3:15])=O>>[S:13]1[CH:15]=[C:9]([CH:2]([CH3:3])[C:4]#[N:5])[N:10]=[CH:12]1
Reactant: CC(Cl)c1cscn1
Reactant: CS(C)=O
Reactant: [C-]#N
Agent: [Na+]
Product: CC(C#N)c1cscn1
Temperature: 50 °C

Procedure:
A solution of 7.8 g. of 4-(α-chloroethyl)thiazole is added dropwise to a suspension of 5.2 g. of sodium cyanide in 100 ml. of dimethylsulfoxide. The mixture is heated at 50°C. for two hours, then diluted with 150 ml. of a 5% aqueous sodium carbonate solution and extracted with ether. The extract is dried and concentrated to give α-(4-thiazolyl)-propionitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([OH:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]1.[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:27]=1.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52]O)[CH2:47][CH2:46]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:26]([N:9]1[CH:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([O:20][CH2:52][CH2:51][N:48]2[CH2:49][CH2:50][O:45][CH2:46][CH2:47]2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:27]
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: OCCN1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1C(OCCN2CCOCC2)=C(c2ccc(Cl)cc2)N(c2ccccc2Cl)N1CC
Yield: 100 %

Procedure:
To a solution of 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-ethoxycarbonyl-4-hydroxy-1H-pyrazole (200 mg, compound obtained in Reference Example 1 (4)) in tetrahydrofuran (4 mL) was added triphenylphosphine (208 mg) and 2-morpholino-ethanol (96 μL) and the mixture was stirred. Thereto was added dropwise diisopropyl azodicarboxylate (154 μL) at 0° C. under nitrogen-gas atmosphere and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=67/33 to 30/70) to obtain ethyl 1-(2-chlorophenyl)-5-(4-chlorophenyl)-3-ethoxycarbonyl-4-(2-morpholinoethoxy)-1H-pyrazole (463 mg, yield: 100%) as a colorless viscidity.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][OH:50])[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH3:2].[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][OH:50])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Product: N
Temperature: 70 °C
Yield: 67.3 %

Procedure:
A solution of Intermediate 5c (1.60 g, 4.40 mmol) and Intermediate 29c (1.85 g, 4.40 mmol) in dioxane (20 mL) was treated with DIPEA (1.15 mL, 6.60 mmol) and the reaction mixture was heated at 70° C. for 36 h. The mixture was concentrated in vacuo and the residue was dissolved in DCM (150 mL) and washed with water (2×75 mL) and brine (75 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo and the foam obtained purified by FCC, using 0-5% MeOH in DCM then 0-5% [2M NH3 in MeOH] in DCM to afford the title compound as a yellow foamy solid (0.94 g, 85%). LCMS (Method 3): Rt 2.76 min, m/z 635 [MH+].
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl-].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH+:19]([CH3:21])[CH3:20].O.[OH-].[Na+]>CS(C)=O>[CH3:20][N:19]([CH3:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][S:8][C:6]1[NH:5][C:4](=[O:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Reactant: C[NH+](C)c1ccccc1CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(=O)[nH]c(SCc2ccccc2N(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
After dissolving 0.71 g (5 mmol) of 6-methyl-2-thiouracil [Ann. 236, 1 (1986)] and 1.03 g (5 mmol) of (2-chloromethylphenyl)-dimethylammonium chloride (J. Chem. Soc. 1954, 4127) in 10 ml of dimethylsulfoxide, the reaction mixture is stirred at room temperature for 1 hour and then poured into 60 ml of water. After adjusting the pH value of the mixture to 6-8 by adding aqueous 1 N sodium hydroxide solution the precipitate is filtered and the crude base (1.3 g) is recrystallized from benzene to give 1.08 g (78.4%) of the title compound, m.p.: 152°-154° C. (white crystals).
Reaction SMILES: [CH2:1]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10](=[O:11])[O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I-:18].[Na+].C[Si](Cl)(C)C.[CH2:25](O)[CH3:26]>C(#N)C.C(OCC)C>[I:18][CH2:25][CH2:26][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:10]([O:9][CH2:8][CH3:7])=[O:11]
Reactant: [I-]
Reactant: O=C1CCCCCCCCCCCCCCO1
Reactant: CCO
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)CCCCCCCCCCCCCCI
Temperature: 25 °C
Yield: 81 %

Procedure:
150.3 g (0.63 mol) of cyclopentadecanolide were dissolved in 500 ml of acetonitrile under a nitrogen atmosphere, and 229.0 g (1.53 mol) of sodium iodide were added. 170 ml (1.34 mol) of trimethylsilyl chloride were added dropwise through a septum. The mixture was heated under reflux for 18 hours. 158.5 g (3.44 mol) of ethanol were cautiously added to the boiling reaction mixture, which was heated under reflux for a further 2 hours and then allowed to cool to room temperature. 500 ml of diethyl ether were added and the mixture was extracted three times with 500 ml of 1N sodium hydroxide solution each time. The aqueous phases were back-extracted with 300 ml of diethyl ether, and the solvent was removed from the combined organic phases in vacuo. The residue was crystallized from methanol twice at −20° C. Drying in vacuo for several days resulted in 202.3 g (0.51 mol, 81%) of ethyl 15-iodopentadecanoate. Although the product was obtained in good purity, it had an intense odor of precursor owing to very small amounts of lactone (perfumed!).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])[CH:17]=[CH:16][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(O)(=O)C.[BH4-].[Na+]>O>[F:5][C:6]1[CH:19]=[C:18]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])[CH:17]=[CH:16][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.8 %

Procedure:
To a dimethyl sulfoxide (30.0 mL) solution of 2-(2-fluoro-4-((E)-2-nitro-vinyl)-phenoxymethyl)-pyridine (3.00 g, 10.9 mmol) described in Manufacturing Example 87-1-2 and acetic acid (3.00 mL) was added sodium borohydride (660 mg, 17.4 mmol) at room temperature while cooling appropriately under nitrogen atmosphere, which was stirred for 20 minutes at room temperature. Water was then added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was crystallized with a tetrahydrofuran-ethyl acetate-heptane system and filtered to obtain the title compound (1.50 g, 49.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:28])[NH:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][NH:24][CH2:25]3)=[CH:20][CH:19]=2)[CH:11]=1)=[O:7].Br[CH2:35][CH:36]([F:38])[F:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:37][CH:36]([F:38])[CH2:35][N:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][C:18]([NH:17][C:16]([C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=3)[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:28])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CNCC4)c2)cc1OC
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3ccc4c(c3)CN(CC(F)F)CC4)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolved 3,4-dimethoxy-N-[3-(1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzyl]-benzamide (50.0 mg, 0.12 mmol) in 1 mL of DMF. Added 2-bromo-1,1-difluoro-ethane and (0.02 mL, 0.20 mmol) K2CO3 (50.0 mg, 0.36 mmol). The mixture was stirred at room temperature overnight. LC-MS indicated low conversion to alkylated product. Heated the mixture to 60° C. for 8 h with continued low conversion, thereafter it was heated to 75° C. for 48 h. LC-MS indicated the desired product. Dissolved in 5 mL of DMF and purified via prep HPLC (5%-95% CH3CN/H2O) to give 28.1 mg of N-{3-[2-(2,2-difluoro-ethyl)-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl]-benzyl}-3,4-dimethoxy-benzamide. MS, electrospray 510.4 (M+H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([F:20])[C:10]2=1.CO.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:17](=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)[NH:16][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([F:20])[C:10]2=1
Reactant: Fc1cncc2[nH]c3ccc(Cl)cc3c12
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=[N+]([O-])c1cc(Cl)cc2c1[nH]c1cncc(F)c12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 102.2 %

Procedure:
Sodium nitrate (1.5 eq, 53 mmol, 4.5 g) was added portionwise to a solution of Intermediate 65 (1.0 eq, 35 mmol, 7.8 g) in trifluoroacetic acid (200 mL) and the resulting mixture heated at 70° C. for 3 h. After cooling to RT the trifluoroacetic acid was removed on a rotary evaporator to afford a crude solid which was suspended in a small volume of methanol and added dropwise to a vigorously stirred mixture of saturated sodium bicarbonate solution (500 mL). The resulting slurry was stirred for 15 min then the precipitated solids were collected by suction filtration, washed with water (300 mL) and then dried in vacuo to afford 6-chloro-4-fluoro-8-nitro-9H-β-carboline (about 9.5 g) which was used in the subsequent step without further purification. Retention Time (LC, method: ammonium acetate standard): 1.79 min. MS (M+H+): 266
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]2[N:9]([CH3:15])[C:10](=[O:14])[C:11]([CH3:13])([CH3:12])[C:6]2=[CH:5][CH:4]=1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[CH3:15][N:9]1[C:7]2=[N:8][C:3]([NH:2][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)=[CH:4][CH:5]=[C:6]2[C:11]([CH3:12])([CH3:13])[C:10]1=[O:14]
Reactant: CN1C(=O)C(C)(C)c2ccc(N)nc21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3cccnc3)nc21

Procedure:
Prepared in analogy to example 2 using 6-amino-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2-one hydrochloride (example 76c) and nicotinoyl chloride hydrochloride. The title compound was obtained as light yellow solid.