Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[C:25](=[O:30])[NH:26][CH2:27][C:28]#[N:29])=[CH:13][C:12]=1[F:31])(C)(C)C.[CH3:33][S:34]([OH:37])(=[O:36])=[O:35].CCOCC>O1CCCC1>[S:34]([OH:37])(=[O:36])(=[O:35])[CH3:33].[C:28]([CH2:27][NH:26][C:25]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[CH2:18][S:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][NH2:7])=[C:12]([F:31])[CH:13]=1)=[O:30])#[N:29]
Reactant: CC(C)(C)OC(=O)NCCSc1ccc(SCC2CCCCC2C(=O)NCC#N)cc1F
Agent: CS(=O)(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCNC(=O)C1CCCCC1CSc1ccc(SCCN)c(F)c1

Procedure:
(2-{4-[2-(Cyanomethylcarbamoyl)-cyclohexylmethylsulfanyl]-2-fluorophenylsulfanyl}-ethyl)-carbamic acid tert-butyl ester was dissolved in tetrahydrofuran (3 mL) and methanesulfonic acid (0.428 g, 6.6 mmol) was added. The reaction mixture was stirred at room temperature overnight, whereupon ether (100 mL) was added. The supernatant was discarded. The residue was triturated three times with ether (50 mL) then 10% tetrahydrofuran/ether, resulting in a white solid, N-cyanomethyl 2-[4-(2-aminoethylsulfanyl)-3-fluoro-phenylsulfanylmethyl]-cyclohexanecarboxamide mesylate, which was isolated by filtration in near quantitative mass recovery, with a small amount of t-butyl amide present as an inseparable impurity, resulting from addition of tert-butanol across the nitrile group under the acidic Boc-cleavage conditions. MS [ESI, (M+H)+] m/z=412 amu.
Reaction SMILES: [OH:1][C@@H:2]([C@H:45]([OH:52])[C@@H:46]([OH:51])[C@@H:47]([OH:50])[CH2:48][OH:49])[CH2:3][NH:4][C:5]([CH2:7][CH2:8][C@H:9]([NH:14][C:15](=[O:44])[C@@H:16]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:17][CH2:18][C:19](=[O:32])[NH:20][CH2:21][C@@H:22]([OH:31])[C@H:23]([OH:30])[C@@H:24]([OH:29])[C@@H:25]([OH:28])[CH2:26][OH:27])[C:10]([O:12]C)=[O:11])=[O:6].[OH-].[Li+]>O1CCCC1.CO>[OH:1][C@@H:2]([C@H:45]([OH:52])[C@@H:46]([OH:51])[C@@H:47]([OH:50])[CH2:48][OH:49])[CH2:3][NH:4][C:5]([CH2:7][CH2:8][C@H:9]([NH:14][C:15](=[O:44])[C@@H:16]([NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[CH2:17][CH2:18][C:19](=[O:32])[NH:20][CH2:21][C@@H:22]([OH:31])[C@H:23]([OH:30])[C@@H:24]([OH:29])[C@@H:25]([OH:28])[CH2:26][OH:27])[C:10]([OH:12])=[O:11])=[O:6]
Reactant: COC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC[C@H](NC(=O)[C@H](CCC(=O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO)NC(=O)OCc1ccccc1)C(=O)O)NC[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
The product of step 11B is dissolved in tetrahydrofuran/methanol (1:1) and treated with excess 3N aqueous lithium hydroxide. The reaction is followed by HPLC for disappearance of starting material. The reaction is concentrated, diluted with additional water, and purified by passage down an acidic ion exchange column. The product fractions are lyophilized to afford the product as a solid.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1.[CH3:14]O>>[Cl:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=1
Reactant: O=C(O)c1csc(Cl)n1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
Thionyl chloride (4.4 mL, 61 mmol) was added dropwise to a solution of 2-chlorothiazole-4-carboxylic acid (2.00 g, 12.2 mmol) in MeOH (40 mL) at 0° C., and the reaction mixture was allowed to warm to rt. After stirring overnight, the reaction mixture was concentrated under reduced pressure. The resulting solid was recrystallized from EtOH/H2O (1:1), yielding 1.40 g (65%) of the title compound as an orange solid. LC-MS: RT=6.17 min, [M+H]+=178.1.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=[C:12]([CH3:22])[C:8]=2[C:9]([NH2:11])=[O:10])[CH2:3]1.[OH-].[Na+].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>O1CCCC1.C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:11][C:9](=[O:10])[C:8]2[C:12]([CH3:22])=[CH:13][C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:15][C:7]=2[N:4]2[CH2:5][CH2:6][C@@H:2]([F:1])[CH2:3]2)=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCOCC2)cc(N2CC[C@@H](F)C2)c1C(N)=O
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)cc(N2CC[C@@H](F)C2)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
To a stirred solution of 2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzamide (0.13 g, 0.42 mmol) in tetrahydrofuran/benzene (1:1) (6 ml) is added tetrabutylammonium hydrogen sulfate (15.0 mg, 0.04 mmol) followed by the addition of 15% aqueous sodium hydroxide (3.7 ml) at room temperature. A solution of 4-chloro-benzyl bromide (0.087 g, 0.42 mmol) in tetrahydrofuran (1 ml) is slowly added to the solution and the resulting mixture is heated to 80° C. for 45 min. The mixture is cooled to room temperature and extracted with ethyl acetate (3×10 ml). The combined organic layers are washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to get crude product, which is purified by flash column chromatography (silica gel, 10% acetone/hexane) to yield N-[(4-chlorophenyl)-methyl]-2-[(3R)-3-fluoro-pyrrolidin-1-yl]-6-methyl-4-morpholin-4-yl-benzamide (example 38) (0.04 g, 0.09 mmol, 22%). [M+H]+ 432.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20]([O:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[C:26](F)[C:25]=1[N+:33]([O-:35])=[O:34])[CH:21]=[CH2:22]>C1COCC1>[CH2:20]([O:23][C:24]1[C:25]([N+:33]([O-:35])=[O:34])=[C:26]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:9])[C:27]([F:31])=[C:28]([F:30])[CH:29]=1)[CH:21]=[CH2:22]
Reactant: Nc1ccc(Br)cc1F
Reactant: C=CCOc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a solution of 4-bromo-2-fluoro-phenylamine (0.815 g, 4.3 mmol) in THF (50 mL) was dropwise added LHMDS solution (5.6 mL, 5.6 mmol, 1 M in THF) at −78° C. After stirring for 1 h at −78° C., a solution of 1-allyloxy-3,4,5-trifluoro-2-nitro-benzene (1.1 g, 4.7 mmol) in THF (10 mL) was dropwise added into the reaction mixture, which was stirred at −78° C. for 1 h and at room temperature for 16 h. The progress of reaction was monitored by 1H NMR. After completion, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over anhydrous Na2SO4 and concentrated. The residue obtained was triturated with hexane to yield (3-allyloxy-5,6-difluoro-2-nitro-phenyl)-(4-bromo-2-fluoro-phenyl)-amine as a yellow solid (724 mg). 1H-NMR (400 MHz, CDCl3): δ 4.55 (2H, d, J=5.6), 5.32-5.36 (2H, m), 5.42 (1H, d), 6.02-6.08 (1H, m), 6.35 (1H, t, J=8.8), 6.60-6.65 (1H, m), 7.06 (1H, d, J=8.4), 7.23 (1H, dd, J=2.0, 10.4).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH:17]([OH:18])[CH2:16][O:15][CH2:14]3)[N:11]=[CH:10][C:9]=2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]([F:24])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:49]1[C:50]([O:57][CH3:58])=[N:51][C:52]([CH3:56])=[CH:53][C:54]=1[CH3:55]>CN(C=O)C.O>[F:24][C:4]1[CH:3]=[C:2]([C:49]2[C:50]([O:57][CH3:58])=[N:51][C:52]([CH3:56])=[CH:53][C:54]=2[CH3:55])[CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)[N:11]=[CH:10][C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1cnn(C2COCC2O)c1-c1ccc(Br)cc1F
Reactant: COc1nc(C)cc(C)c1Br
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C2COCC2O)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1F
Temperature: 90 °C

Procedure:
Ethyl 5-(4-bromo-2-fluorophenyl)-1-[(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (3.8 g), bis(pinacolato)diboron (2.90 g), potassium acetate (2.80 g) and Pd(dppf)Cl2-DCM complex (480 mg) were added to DMF (38.3 mL), and the mixture was stirred at 90° C. in a nitrogen atmosphere. After stirring the reaction mixture for about two hours, a solution of 3-bromo-2-methoxy-4,6-dimethylpyridine obtained in Preparation Example 26 (3.09 g) in DMF (15 mL), and water (22 mL) were added, and the mixture was warmed to 120° C. and further stirred for about five hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was passed through a silica gel pad (NH silica gel, eluting with ethyl acetate). The filtrate was concentrated to about 200 mL and then partitioned by adding brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 70% to 90%) to give the title compound (2.26 g).
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17]C)[CH:11]=2)=[O:7].B(Br)(Br)Br>O>[CH3:4][O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([OH:17])[CH:11]=2)=[O:7]
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(O)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 84.7 %

Procedure:
To a dichloromethane (10 mL) solution of 6-methoxy-1H-indole-2-carboxylic acid methyl ester (500 mg, 2.44 mmol) was added boron tribromide (12.2 mL, 12.2 mmol) at −78° C., which was stirred for 50 minutes at 0° C. under nitrogen atmosphere. To the reaction solution was added water at 0° C. followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (395 mg, 85%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].BrCC1OC(C(F)(F)F)=CC=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:25]1=[O:45].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[O:45]=[C:25]1[C:26]2([C:44]3[C:35](=[CH:36][C:37]4[O:42][CH2:41][CH2:40][O:39][C:38]=4[CH:43]=3)[O:34][CH2:33]2)[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]1[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: COC(=O)c1cccc(CBr)c1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using methyl 3-bromomethylbenzoate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, methyl 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoate was obtained (99%) as a colorless solid: mp 89-97° C. (ethyl acetate/diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.98-7.95 (m, 2H), 7.51-7.42 (m, 2H), 7.19-7.14 (m, 2H), 7.03-7.01 (m, 1H), 6.73-6.70 (m, 1H), 6.50 (s, 1H), 6.27 (s, 1H), 5.19-5.13 (m, 1H), 4.95-4.92 (m, 1H), 4.84-4.79 (m, 1H), 4.67-4.64 (m, 1H), 4.19-4.11 (m, 4H), 3.90 (s, 3H) 13C NMR (75 MHz, CDCl3) δ 177.6, 166.7, 153.3, 144.7, 141.7, 138.4, 136.1, 132.3, 131.7, 130.8, 129.2, 128.9, 128.1, 124.0, 123.6, 120.9, 111.6, 109.2, 99.4, 80.2, 64.5, 63.9, 58.1, 52.3, 43.8, 29.7; MS (ES+) m/z 443.8 (M+1).
Reaction SMILES: C[N:2]([CH2:4][CH2:5][CH2:6][C@@:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:11][CH2:10][C:9]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:8]1=2)C.C(O)(C(O)=O)=O.O=C(C(=O)O)O>O>[NH2:2][CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:8]2[C:9](=[CH:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=2)[CH2:10][O:11]1
Reactant: CN(C)CCC[C@@]1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Agent: O=C(O)C(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)COC2(CCCN)c1ccc(F)cc1

Procedure:
Sodium cyanoborohydride (0.34 g. 5.4 mmol) was added to a mixture of 1-(3-Aminopropyl)-1-(4-fluorophenyl)-1,3-dihydro-5-isobenlzofiurancarbonitrile (0.80 g, 2.7 mmol) and formaldehyde (0.44 mL, 5.4 mmol, 37% in H2O) in methanol (10 mL). The resulting mixture was stirred at room temperature for 3 h, then was added more sodium cyanoborohydride (0.17 g, 2.7 mmol) and formaldehyde (0.22 mL, 2.7 mmol). After stirring at room temperature for 1 h, the mixture was quenched with H2O and extracted with Et2O. The organic extracts were dried and evaporated. Silica gel chromatography (EtOAc, heptane, triethylamine 75:25:1) of the residue gave the crude product, which was isolated as the oxalate salt from acetone (0.31 g, 0.8 mmol, 30%). The NMR-spectra were identical with those obtained from citalopram oxalate prepared in example 2. Anal. (C20H21N2O, C2H2O4, ¼ H2O) calcd. C: 63.06; H: 5.67; N: 6.69. Found C: 63.28; H: 5.64; N: 6.67.
Reaction SMILES: Cl[C:2]1[C:7]2=[CH:8][C:9]3[C:14]([N:6]2[N:5]=[C:4]([S:15][CH3:16])[N:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[BH4-].[Na+]>C(O)(C)C>[CH3:16][S:15][C:4]1[NH:3][CH2:2][C:7]2=[CH:8][C:9]3[C:14]([N:6]2[N:5]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CSc1nc(Cl)c2cc3ccccc3n2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CSC1=Nn2c(cc3ccccc32)CN1
Temperature: 55 °C

Procedure:
4-Chloro-2-methylsulfanyl-[1,2,4]triazino[1,6-a]indole (1.00 g, 4.00 mmol) was suspended in isopropyl alcohol (13 mL) at room temperature. Sodium borohydride (0.318 g, 8.41 mmol) was added and the reaction mixture was heated at 55° C. for 3 hours. The reaction was allowed to cool to room temperature, then aqueous NaHCO3/dichloromethane extraction work-up, drying and evaporation of solvent afforded 2-methylsulfanyl-3,4-dihydro-[1,2,4]triazino[1,6-a]indole. 1H-NMR (CDCl3) δ 7.63 (d, J=8.1 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.18 (m, 1H), 7.08 (m, 1H), 6.15 (s, 1H), 4.73 (s, 2H), 4.63 (br s, 1H), 2.60 (s, 3H); LC/MS (ESI+): 218.5 (M+H). Benzene (30 mL) was added, and the solution was treated with manganese(IV) oxide (1.39 g, 16.0 mmol). The reaction mixture was stirred overnight. The solids were removed by filtration through Celite and were washed with dichloromethane. The solvent was removed under vacuum to afford 2-methylsulfanyl-[1,2,4]triazino[1,6-a]indole (0.79 g, 92% over two steps), which was used in the next step without further purification. 1H-NMR (CDCl3) δ 9.05 (s, 1H), 8.15 (dd, J=8.5, 0.8 Hz, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.47 (m, 1H), 7.39 (m, 1H), 6.99 (s, 1H), 2.68 (s, 3H); LC/MS (ESI+): 216.5 (M+H).
Reaction SMILES: [CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12](O[C:15](=[O:16])[CH:6]21)=[O:13])[CH:2]=[CH2:3].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12](=[O:13])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]3[C:12](=[O:13])[CH:7]4[CH:6]([C:5]5([CH2:4][CH2:1][CH:2]=[CH2:3])[CH2:11][CH:8]4[CH:9]=[CH:10]5)[C:15]3=[O:16])[C:15](=[O:16])[CH:6]21)[CH:2]=[CH2:3]
Reactant: C=CCCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NCCCCCCN
Product: C=CCCC12C=CC(C1)C1C(=O)N(CCCCCCN3C(=O)C4C5C=CC(CCC=C)(C5)C4C3=O)C(=O)C12
Temperature: 130 °C

Procedure:
300 g of allylmethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are taken and heated to 130° C., and 79.9 g of melted hexamethylene diamine are added dropwise, with stirring. Water is removed by distillation, the temperature is raised to 180° C. and the pressure is reduced to 53 Pa. 180° C. and 53 Pa are maintained for 15 minutes. This gives 345 g (97% of theory) of a brown, viscous resin having a viscosity of 1.356 Pa.s at 80° C.
Reaction SMILES: [CH3:1]/[C:2](=[CH:11]\[N:12]1[CH2:17][CH2:16][CH2:15]CC1)/[C:3]([NH:5][C:6](=[O:10])OCC)=[S:4].Cl.[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32](CCCN)[CH2:31][CH2:30]2)[CH:26]=[C:25]([C:39]([F:42])([F:41])[F:40])[N:24]=1)([CH3:22])([CH3:21])[CH3:20].CN1CCOCC1>CO>[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH2:15][CH2:16][CH2:17][N:12]3[CH:11]=[C:2]([CH3:1])[C:3]([SH:4])=[N:5][C:6]3=[O:10])[CH2:33][CH2:34]2)[CH:26]=[C:25]([C:39]([F:40])([F:41])[F:42])[N:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1nc(N2CCN(CCCN)CC2)cc(C(F)(F)F)n1
Reactant: CCOC(=O)NC(=S)/C(C)=C/N1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1cn(CCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)nc1S
Yield: 40.9 %

Procedure:
0.7 g (2.7 mmol) of ethyl (2E)-2-methyl-3-piperidin-1-ylprop-2-enethioylcarbamate (WO 00/61579), 0.9 g (2.6 mmol) of 3-{4-[2-tert-butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}propan-1-amine hydrochloride from Example 1.2 and 0.6 g (5.5 mmol) of N-methylmorpholine in 20 ml of methanol were stirred at room temperature under a nitrogen atmosphere for 12 hours. Insolubles were removed by filtration, washed three times with methanol and water and then recrystallized from ethyl acetate. Drying in vacuo at 50° C. resulted in 0.5 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11](Cl)(=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
To 5.0 g of para-nitrophenol in 60 ml of chloroform+ ether (1:1) are added while cooling with ice first 9.4 g of palmitoyl chloride and then 5.0 ml of triethylamine. After having been refluxed for 2 hours, the batch is dissolved in ethyl acetate, and the organic phase is washed with 0.5N-potassium carbonate and water, dried over sodium sulfate and evaporated. On crystallization from ether+petroleum ether, lamellae are obtained which melt at 64°-65°C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[C:12]([NH2:27])[N:11]=2)=[CH:6][C:5]=1[F:28]>C1COCC1>[NH2:27][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[C:5]([F:28])[CH:6]=2)[C:15]([C:16]#[C:17][C:18]2[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=2)=[C:14]([CH2:25][CH3:26])[N:13]=1
Reactant: CCc1nc(N)nc(-c2ccc(C(=O)OC)c(F)c2)c1C#Cc1ccc(N)nc1
Solvent: C1CCOC1
Product: CCc1nc(N)nc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 630 mg (1.6 mmol) 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-fluoro-benzoic acid methyl ester using 1.6 mL (1.6 mmol) 1 N NaOH in 10 mL THF. The precipitate is collected by filtration and washed with THF. Yield: 580 mg (96%).
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClC(Cl)C>[CH:1]1[C:9]([NH:10][C:18](=[O:20])[CH3:19])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Solvent: CC(Cl)Cl
Product: CC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCC1
Yield: 23.7 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indole-2-amine (0.10 g, 0.44 mmol), acetic anhydride (0.042 mL, 0.44 mmol) and poly-(4-vinylpyridine) (600 mg) in dichloroethane (15 mL) provided 28 mg of N-4,5,8,9,10,11-hexahydro-7H-cyclohepta[b]pyrrolo[3,2,1-hi]indol-2-ylacetamide. MS m/z 269; HPLC purity 100% at 210-370 nm, 9.2 min.; 98.7% at 248 nm, 9.2 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C17H20N2O+H+, 269.16484; found (ESI, [M+H]+), 269.1651.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[CH:10]=[CH:9][C:8]=2[OH:23])=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[C:32](F)=[CH:33][C:34]([F:57])=[C:35]([S:37]([N:40]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:41]2[S:42][CH:43]=[N:44][N:45]=2)(=[O:39])=[O:38])[CH:36]=1>CS(C)=O>[Cl:30][C:31]1[C:32]([O:23][C:8]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[N:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[CH:33][C:34]([F:57])=[C:35]([S:37]([N:40]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=2[O:55][CH3:56])[C:41]2[S:42][CH:43]=[N:44][N:45]=2)(=[O:38])=[O:39])[CH:36]=1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)nc2)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(-c4ccc(C(F)(F)F)nc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
2-(Pyridazin-4-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)phenol (Preparation 59, 360 mg, 1.134 mmol) was dissolved in DMSO (6 mL) and potassium carbonate (313 mg, 2.27 mmol) was added followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 524 mg, 1.134 mmol). The reaction was stirred at room temperature for 18 hours and then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified on silica gel by Biotage (20% to 100% EtOAc in heptane over 20 CV) to give the title compound (501 mg, 58%) as yellow foam.