Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH3:30][N:31]([CH2:33][CH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)[CH3:32].O>C1COCC1>[CH3:30][N:31]([CH2:33][CH:34]1[CH2:39][CH2:38][CH:37]([CH:2]=[O:3])[CH2:36][CH2:35]1)[CH3:32]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(C)CC1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC1CCC(C=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (25.7 g, 75 mmole) was suspended in absolute THF (100 ml) under argon, potassium tert-butylate (8.42 g, 75 mmole) dissolved in absolute THF (70 ml) was added dropwise, and then stirred for 15 minutes at 0° C. The corresponding 4-[dimethylaminomethyl]-cyclohexanone 8 (50 mmole), dissolved in absolute THF (75 ml), was then added dropwise to the above solution and stirred overnight at RT. The mixture was hydrolysed by adding dropwise water (38 ml) and 6N HCL 112 ml) while cooling with iced water. After stirring for one hour at RT the mixture was extracted with ether (10×50 ml), the aqueous phase was adjusted to pH 11 with 5N NaOH, shaken with ethyl acetate (3×50 ml), dried over Na2SO4, and concentrated by evaporation in vacuo. The crude product was purified by flash chromatography with ethyl acetate/cyclohexane (1:1). As a rule two diastereomers were obtained in different ratios.
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>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>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:18]([C:17](=[O:38])[N:14]2[CH2:15][CH2:16][N:11]([C:3]3[C:2]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:12][CH2:13]2)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:32][CH:33]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 2 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.150 g, 0.248 mmol, see Example 4), phenylboronic acid (0.0363 g, 0.298 mmol), Pd(PPh3)4 (0.0143 g, 0.0124 mmol) and 10% K2CO3 (aq., 0.517 mL, 0.372 mmol) were placed in Ar degassed 2:1 toluene:EtOH and heated to 80° C. overnight. The reaction was cooled to room temperature, diluted with water, and extracted with DCM. The combined organic fractions were dried, filtered, concentrated, and purified (500:7 DCM:MeOH) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate (0.003 g, 2.0% yield)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1>COC1C=CC(CNC)=CC=1>[NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:7]=1
Reactant: Cn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(Cl)cc21
Agent: CNCc1ccc(OC)cc1
Product: Cn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnccc21
Temperature: 200 °C
Yield: 139.2 %

Procedure:
3-(5-Amino-2,4-difluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.4 g, 7.5 mmol) and 4-methoxy-N-methylbenzylamine (10 mL) were combined in a sealed vessel and heated to 200° C. overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography to give 7-(4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 91% yield), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[Na+].C(O)C>O1CCCC1>[CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc(F)cc2)[nH]c1CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1[nH]c(-c2ccc(F)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A mixture of ethyl 5-ethyl-2-(4-fluorophenyl)imidazol-4-carboxylate (2.81 g), 4N aqueous sodium hydroxide solution (14 ml), ethanol (35 ml) and tetrahydrofuran (15 ml) was stirred at room temperature overnight, followed by refluxing for 3 hours. 4N aqueous sodium hydroxide solution (28 ml) was added to the mixture and the mixture was refluxed overnight. After cooling, the reaction mixture was concentrated under reduced pressure and neutralized by 10% hydrochloric acid, and precipitated solid was collected by filtration. The solid was dissolved in tetrahydrofuran, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with diethyl ether to obtain first crop of 5-ethyl-2-(4-fluorophenyl)imidazol-4-carboxylic acid (1.06 g) as colorless powder. Moreover, the filtrate was purified by HP-20 resin (trade name, available from Nippon Rensui K.K.) (solvent: water→methanol) to give second crop of 5-ethyl-2-(4-fluorophenyl)imidazol-4-carboxylic acid (1.60 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[CH2:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[C:24](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:24])[N:13]=[C:12]2[CH2:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cc1n[nH]c2ccc(OCc3ccccc3)cc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)Cc1nn(C)c2ccc(OCc3ccccc3)cc12
Temperature: 70 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
To a solution of the product from Step A (1.2 g, 4.28 mmol) in DMF (10 ml) was added iodomethane (0.53 ml, 8.6 mmol) and potassium carbonate (1.2 g, 8.6 mmol); this mixture was stirred for 16 h at 70° C. After adding water (15 ml) and ethyl acetate (15 ml) to the reaction mixture, the aqueous layer was separated and extracted with ethyl acetate (3×20 ml). The combined extracts were washed with brine, dried (MgSO4), and evaporated to a residue which was puified by chromatography (silica, ethyl acetate/hexane, 1:1) to give a viscous oil (0.6 g): APCl/LCMS m/z 295 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C([O-])(=O)C.[Na+]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([C:27]([N:26]([CH3:30])[CH3:25])=[O:28])[OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: COc1ccc2c(c1)c(CN(O)C(=O)N(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 30 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine is reacted with 14 eq of dimethylcarbamoyl chloride and 3.5 eq of sodium acetate (added in portions). The crude product is purified by column chromatography (silica gel, 1:4/ethyl acetate:methylene chloride). Recrystallization from methylene chloride:hexane, followed by column chromatography (silica gel, ether) and recrystallization from methanol:water gives pure 1-(4-chlorobenzoyl)-N-[(dimethylamino)carbonyl]-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine (30%); mp 173°-174° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13].Br[CH2:17][C:18](=[O:32])[CH2:19][C@H:20]1[C@H:25]([O:26][CH3:27])[CH2:24][CH2:23][CH2:22][N:21]1[C:28]([O:30][CH3:31])=[O:29]>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([CH2:17][C:18](=[O:32])[CH2:19][C@H:20]1[C@H:25]([O:26][CH3:27])[CH2:24][CH2:23][CH2:22][N:21]1[C:28]([O:30][CH3:31])=[O:29])[C:6]2=[O:13]
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2ccc(C(F)(F)F)cc12
Product: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2ccc(C(F)(F)F)cc2c1=O
Yield: 24 %

Procedure:
By the method of Example 4, 6-trifluoromethyl- quinazolin-4-(3H)-one and methyl trans-2-(3-bromo-2-oxoproyl)3-methoxypiperidine-1-carboxylate were converted into the title compound in 24% yield; m.p. 137°-140° C. 1H-NMR(CDCl3) 1.4-1.9 (m, 4H), 2.9 (d, 2H), 3.3 (s, 3H), 3.5-3.9 (m,4H), 3.7 (s, 3H), 5.2 (s, 2H), 7.7-8.7 (m,4H).
Reaction SMILES: [C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([SH:12])=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2].[OH-].[Na+].Cl.[CH3:19][O:20][C:21]1[C:22]([CH2:29]Cl)=[N:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O.CO>[C:1]([C:5]1[C:14]([CH3:15])=[CH:13][C:8]2[NH:9][C:10]([S:12][CH2:29][C:22]3[C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][N:23]=3)=[N:11][C:7]=2[CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COc1ccnc(CCl)c1OC
Reactant: COC(=O)c1cc2nc(S)[nH]c2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2nc(SCc3nccc(OC)c3OC)[nH]c2cc1C
Reaction time: 1 h
Yield: 92 %

Procedure:
5-Carbomethoxy-6-methyl-2-mercapto-1H-benzimidazole (0.67 g, 0.003 mol) and NaOH (0.12g, 0.003 mol) in H2O (0.6 ml) were dissolved in CH3OH (15 ml). 3,4-dimethoxy-2-chloromethylpyridine hydrochloride, (=0.0036 mol) as a crude material in CH3OH (10 ml) and NaOH (0.144 g, 0.0036 mol) in H2O (0.72 ml) were added. The mixture was heated to reflux and the reflux was continued for 1 hour. CH3OH was evaporated off and the crude material was purified by chromatography on a silica column using CH2Cl2 --CH3OH (98-2) as eluent, giving (1.03 g, 92%) of the pure title compound.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=[C:13]3[C:12]([C:20]3[CH:21]=[N:22][N:23]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[H-].[Na+].[CH3:46][Si:47]([CH2:50][CH2:51][O:52][CH2:53]Cl)([CH3:49])[CH3:48].C(OCC)(=O)C>CN(C=O)C>[Br:19][C:17]1[CH:18]=[C:13]2[C:12]([C:20]3[CH:21]=[N:22][N:23]([C:25]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:24]=3)=[CH:11][N:10]([CH2:53][O:52][CH2:51][CH2:50][Si:47]([CH3:49])([CH3:48])[CH3:46])[C:14]2=[N:15][CH:16]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)c2cc(Br)cnc21
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of 21 (0.5 g, 0.99 mmol) in DMF (2.5 mL) was added NaH (60% w/w in mineral oil, 59.4 mg, 1.48 mmol) portionwise. Then the reaction mixture was stirred for 0.5 h. SEM-Cl (263 μL, 1.48 mmol) was then added and the reaction mixture stirred overnight. It was poured cautiously onto a stirred mixture of ethyl acetate (20 mL)/sat. aq. NH4Cl (20 mL) and the layers separated. The aqueous layer was extracted with AcOEt (2×30 mL), the combined organic extracts dried (MgSO4) and concentrated. The residue was purified by SGC using AcOEt:hexane (gradient elution up to 8:92, v/v) to give 22 as a white foam (345 mg, 55%); 1H NMR (400 MHz, CDCl3) δ 0.002 (9H, s), 0.97 (t, J=8.3 Hz, 2H), 3.58 (t, J=8.3 Hz, 2H), 5.69 (s, 2H), 7.30 (m, 6H), 7.40 (m, 9H), 7.46 (s, 1H), 7.65 (s, 1H), 7.98 (d, J=0.7 Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])(=[O:12])=[O:11])([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)OCC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccccc1S(=O)(=O)OCC(F)(F)F
Yield: 91.4 %

Procedure:
In a pressure vessel, 107 g of 2,2,2-trifluoroethyl 2-nitrobenzenesulfonate and 8 g of 5% palladium-on-carbon in 300 ml of ethyl acetate was heated to 110° and shaken under 500 psi hydrogen pressure until hydrogen was no longer absorbed. The reaction mixture was cooled and the catalyst filtered off. The filtrate was stripped in vacuo to give 87.5 g of 2,2,2-trifluoroethyl 2-aminobenzenesulfonate as a dark oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH2:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[O:30]1[CH2:33][C:32](=O)[CH2:31]1.C(N(C(C)C)C(C)C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:29]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][NH:27][CH:32]3[CH2:33][O:30][CH2:31]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:28])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCN)c2c1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCCNC3COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a stirred of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]propane-1,3-diamine (84 mg, 0.2 mmol, prepared in analogy to Example 9-3), oxetan-3-one (15 mg, 0.21 mmol) and ethyldiisopropylamine (43 μL, 0.25 mmol) in dichloromethane (10 mL) was added molecular sieves (4 Å, 84 mg) followed by sodium triacetoxyborohydride (63.6 mg, 0.3 mmol). After being stirred at room temperature overnight, another batch of sodium triacetoxyborohydride (63.6 mg, 0.3 mmol) was added and the mixture was heated under reflux for 2 hours. The reaction mixture was cooled, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 26 mg of N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-N′-(oxetan-3-yl)propane-1,3-diamine as a white solid. MS obsd. (ESI+) [(M+H)+] 467, 1H NMR (400 MHz, CD3OD) δ ppm 8.05 (d, J=7.6 Hz, 1 H), 7.87 (d, J=7.6 Hz, 1 H), 7.34 (s, 1 H), 7.68 (t, J=14.8 Hz, 1 H), 7.58-7.51 (m, 2 H), 7.45 (d, 1 H), 5.99 (s, 1 H), 5.24 (s, 2 H), 4.85 (t, J=3.3 Hz, 2 H), 4.85 (t, J=13.6 Hz, 2 H), 4.55 (m, 4 H), 4.06-4.00 (m, 1 H), 3.67 (s, 2 H), 3.50 (t, J=13.2 Hz, 2 H), 2.74 (t, J=13.6 Hz, 2 H), 2.45 (s, 3 H), 1.98-1.91 (m, 2 H).
Reaction SMILES: C(NC(C)C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].C([C:15]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:16]=1[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])C.C(I)C>C1COCC1>[CH:10]([C:15]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:16]=1[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])([CH2:11][CH3:12])[CH3:9]
Reactant: [Li]CCCC
Reactant: CCc1cc(OC)ccc1C(=O)N(CC)CC
Solvent: C1CCOC1
Solvent: CCI
Solvent: CC(C)NC(C)C
Product: CCC(C)c1cc(OC)ccc1C(=O)N(CC)CC
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a mixture of diisopropylamine (40.7 mL, 290 mmol) in THF (800 mL) at -78° C. was added n-BuLi (100 ML, 255 mmol, 2.15M). The mixture was stirred for 1/4 hour, then 2-ethyl-4-methoxy-N,N-diethylbenzamide (235.3 g) in THF (300 mL) was added at -78° C. The mixture was stirred at -78° C. for 2.5 hours, then at 0° C. for 1 hour, and then ethyliodide (23.2 mL) in THF (150 mL) was added over 10 minutes at -78° C. The reaction mixture was stirred for about 1 hour, quenched with saturated NH4Cl (100 mL) and the solvent was removed in vacuo. Ether (500 mL) was added to the residue, the ether layer was washed with saturated NaHCO3 (50 mL), 1N HCl (50 mL), water, then brine, and then the ether layer was dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by distillation under high vacuum (2 mm Hg) to afford 46.6 g (76%) of 2-sec-butyl-4-methoxy-N,N-diethylbenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:13].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:13])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCCCc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1ccc(CCCBr)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
66.0 g (387 mmol) of 3-(p-chlorophenyl)-1-propanol was dissolved in 350 ml of toluene, and a solution having 105 g (387 mmol) of phosphorus tribromide dissolved in 50 ml of toluene, was dropwise added thereto. After the dropwise addition, the internal temperature of the reaction solution was raised to 90° C. and returned to room temperature 3 hours later. 250 ml of a 1N sodium hydroxide aqueous solution was added thereto, followed by shaking. Then, the solution was left to stand still for liquid separation, and the water layer was extracted again with 150 ml of toluene. The toluene layers were put together and washed with 150 ml of a saturated sodium chloride aqueous solution, followed by Celite filtration, and then the solvent was distilled off. The residue was Idistilled to obtain 75.2 g (y 83%) of the desired 3-(p-chlorophenyl)-1-propyl bromide {compound (2)) as a colorless oily substance (85-89° C./0.3 mmHg)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=3)[N:5]2[N:4]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:16][CH:17]=3)[N:5]2[N:4]=1)=[O:30]
Reactant: CSc1ncc2ccc(-c3cccc(CCC#N)c3)n2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3cccc(CCC#N)c3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
1148b Into a round bottom flask, 3-[3-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-propionitrile and Methylene chloride (50 mL) were added. m-Chloroperbenzoic acid (0.366 g, 0.00212 mol) was added portion wise over 20 minutes. The reaction was stirred at room temperature for one hour. The reaction was partitioned with DCM (200 mL) and saturated NaHCO3 (200 mL). The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded 3-[3-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-propionitrile as a yellow solid (540 mg, 98%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[OH:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>CN(C)C(=O)C>[OH:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: OC[C@@H]1CCCN1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCC[C@H]2CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with (S)-2-hydroxymethyl-pyrrolidine in N,N-dimethylacetamide at room temperature to yield trans-N-{4-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-butoxymethyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 521 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:11][CH2:12][CH:13]2[O:17][C:16](=[O:18])[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]2[CH:26]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:26][CH:14]2[N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[C:16](=[O:18])[O:17][CH:13]2[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3[N+](=O)[O-])=CC21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3N)CC21
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of (+/−)-tert-butyl 5-(3-nitropyridin-4-yl)-2-oxo-3a,6,7,7a-tetrahydrobenzo[d]oxazole-3(2H)-carboxylate (1.0 equiv.) in methanol and ethyl acetate (1:1, 0.1 M) was added 10% Pd/C (0.1 equiv.). The resulting mixture was stirred under H2 atmosphere for 6 hours. The solid was removed by filtration. The filtrate was concentrated under reduced pressure to give (+/−)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate (87%), which was used in the next step without further purification. LC/MS (m/z): MH+=334.1, Rt=0.51.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)[CH2:2][CH3:3].[C:14](OC(=O)C)(=[O:16])[CH3:15]>[Cl-].[Zn+2].[Cl-]>[C:14]([C:9]1[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][C:6]([O:12][CH3:13])=[C:7]([O:10][CH3:11])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: CCCc1ccc(OC)c(OC)c1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCc1cc(OC)c(OC)cc1C(C)=O
Yield: 74 %

Procedure:
Following the same procedure as in Example 3 a), a mixture of 18.02 g (0.1 mole) of 4-propyl-1.2-dimethoxybenzene, 5.13 g (0.05 moles) of acetic anhydride and 0.7 g (5 mmoles) of anhydrous zinc chloride was reacted at 80-90° C. for 6 hrs. After washing, separation of the organic phase and evaporation u.v (20° C./21 mbar) a residue was obtained that after purification on silica gel column (eluant n-hexane: ethyl acetate 90/10 v/v) gives 8.0 g (0.037 moles) of 1-acetyl-6-propyl-3,4-dimethoxybenzene.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].C[O-].[Na+].[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][C:15]=1[O:22][CH3:23])([O:12][CH3:13])=[O:11]>CO>[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:2])=[CH:16][C:15]=1[O:22][CH3:23])([O:12][CH3:13])=[O:11]
Reactant: CC(C)[N+](=O)[O-]
Reactant: COC(=O)c1ccc(CBr)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C=O)cc1OC
Yield: 83 %

Procedure:
2-Nitropropane (1.0 g) was added to sodium methoxide (from 0.24 g sodium) in methanol (30 ml) and the solution refluxed for 1/2 hour. 4-Carbomethoxy-3-methoxybenzyl bromide (2.67 g) in methanol was added and the solution refluxed for 1 hour. The methanol was evaporated, the residue partitioned between 2N sodium hydroxide and chloroform. The chloroform layer was shaken with further sodium hydroxide until no more yellow colour was extracted, dried and evaporated to yield the title compound (1.66 g). τ (CDCl3) 6.1 (3H, s), 6.05 (3H, s), 2.4-2.6 (2H, m), 2.07 (1H, d, J=8 Hz), -0.05 (1H, s).