Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:50][CH2:51][CH3:52])[C@@H:5]([N:7]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)[C:8](=[O:38])[C@@H:9]([NH:20]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])[CH3:6])[CH3:2].N1CCCCC1>>[NH2:20][C@@H:9]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])[C:8]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:50][CH2:51][CH3:52])[O:3][CH2:1][CH3:2])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)=[O:38]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1c(C)cc(O)cc1C
Yield: 115.4 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-ylcarbamate (Compound III-18) (512 mg, 0.73 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (404 mg, 115%).
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37](C)[N:38]=[C:12]23)[CH2:7][CH2:6]1.C([Sn](=O)CCCC)CCC.[N:52]([Si](C)(C)C)=[N+:53]=[N-:54].C1(C)C=CC=CC=1>C(OCC)(=O)C>[OH:1][C:2]([CH3:41])([CH3:40])[CH2:3][O:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:54][N:53]=[N:52][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2nc(C)nn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-2-methylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g), dibutyltin oxide (0.046 g), azidotrimethylsilane (1.3 g) and toluene (15 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium fluoride solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 0.93 mL) was added and the mixture was stirred at 70° C. for 1 hr. Ethyl acetate and 1 N hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.033 g, 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH2:18][CH3:19])=[C:16]([C:20](OC)=[O:21])[C:15]([CH2:24][CH3:25])=[N:14]1.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([CH2:18][CH3:19])=[C:16]([CH2:20][OH:21])[C:15]([CH2:24][CH3:25])=[N:14]1
Reactant: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CC)c1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 8 g (20 mmol) of the compound of step B in 50 mL of tetrahydrofuran (THF) was treated at 0° C. with 44.1 mL of 1.5 M diisobutylaluminum hydride in toluene solution over a period of 5 minutes. The reaction was stirred for 2 hours at 0° C. and was then cautiously quenched with water. The product was extracted into ethyl acetate and dried and evaporated to give the title compound in 46% yield. 1H-NMR (CDCl3) δ 1.04 (3H, t, J=7), 1.26 (3H, t, J=7), 2.44 (2H, q, J=7), 2.70 (2H, q, J=7), 4.54 (2H, s), 7.66 (2H, s).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=2)[C:43]1=[O:56]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9](=[O:11])[NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]2[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=2)[C:43]1=[O:56])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: N[C@H]1CCCCN(Cc2cccnc2)C1=O
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(Cc4cccnc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-(pyridin-3-ylmethyl)azepan-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 41 (4.4 mg, 0.020 mmol) to give a white solid (4.5 mg, 47% yield). Anal. Calcd. for C43H53N5O6S m/z 767.7. found: 768.7 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.79 (br. s., 1H), 8.69 (d, J=4.95 Hz, 1H), 8.11 (d, J=7.70 Hz, 1H), 7.70 (dd, J=7.70, 5.50 Hz, 1H), 7.22 (t, J=7.42 Hz, 4H), 7.19-7.10 (m, 6H), 6.98 (d, J=6.60 Hz, 1H), 6.79 (d, J=6.60 Hz, 1H), 5.35-5.28 (m, 1H), 5.15-5.08 (m, 1H), 4.98 (br. s., 1H), 4.88 (d, J=15.40 Hz, 1H), 4.68-4.57 (m, 1H), 4.44 (d, J=15.40 Hz, 1H), 3.67 (s, 3H), 3.60 (dd, J=15.12, 11.82 Hz, 1H), 3.29-3.10 (m, 2H), 2.84-2.77 (m, 3H), 2.77-2.67 (m, 2H), 2.04-1.97 (m, 2H), 1.90-1.48 (m, 13H), 1.26 (t, J=7.15 Hz, 2H), 1.13 (d, J=13.20 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O.[NH2:21][C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][O:25][C:26]2=[O:27].Br(Br)(Br)Br>>[CH3:19][C:9]1([CH3:20])[C:4]2[C:5](=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:12]([NH:21][C:22]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:23]=2[CH2:24][O:25][C:26]3=[O:27])[C:11]([OH:18])([C:14]([F:15])([F:17])[F:16])[CH2:10]1
Reactant: Nc1cccc2c1COC2=O
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Product: COc1cccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c1COC2=O
Yield: 19 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 600 mg of 4-(2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 308 mg of 4-aminophthalide. By reaction of 640 mg of the imine with 7.7 ml of bromine tribromide solution (1 M in dichloromethane), 165 mg of 4-{[4,4-dimethyl-2-hydroxy-5-methoxy-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide is obtained as fraction 1, and 115 mg of 4-{[2,5-dihydroxy-4,4-dimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}-phthalide is obtained as fraction 2.
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][N:13]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH2:14][CH:15]=1)([O-])=O.CCO>CCOC(C)=O.[Pd]>[O:18]1[CH2:19][CH:16]([N:13]2[CH2:14][CH2:15][CH:10]([C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[NH2:1])[CH2:11][CH2:12]2)[CH2:17]1
Reactant: O=[N+]([O-])c1cnccc1C1=CCN(C2COC2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cnccc1C1CCN(C2COC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.5 %

Procedure:
Pd on C, wet, Degussa (240 mg, 0.2255 mmol) was added to a stirred solution of 3-nitro-4-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]pyridine (614 mg, 2.350 mmol) in EtOAc (20 mL)/EtOH (20 mL). The reaction was placed under an atmosphere of hydrogen and stirred at ambient temperature for 15 hours. The catalyst was removed by filtration through a pad of celite and the filtrate concentrated in vacuo to give the 4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-3-amine as a pale yellow solid (518 mg, 95% Yield). MS (ES+) 234.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][C:13](O)=[O:14].[CH3:18][N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:20].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:12][C:13]([N:19]([CH3:20])[CH3:18])=[O:14]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1c(Br)cc(F)c2[nH]cc(CC(=O)O)c12
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(Br)cc(F)c2[nH]cc(CC(=O)N(C)C)c12
Reaction time: 0.08 h
Yield: 72 %

Procedure:
To the solution of 8-9 (11.5 g, 38.0 mmol) in THF (300 mL) was added HATU (22.0 g, 58.0 mmol) Me2NH.HCl (3.1 g, 38.0 mmol) at 0° C. After the mixture was stirred for 5 minutes, DIPEA (12.3 g, 95.3 mmol) was added. The mixture was stirred overnight at room temperature. The volatile was removed and the residue was purified by flash chromatography (Silica gel, DCM/MeOH=50:1) to afford 8-10 (9.0 g, 72%) as white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1([CH3:30])[CH2:15][O:14][C:13]2[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([O:24]C(C)(C)C)=[O:23])[CH:18]=[N:19][C:12]=2[NH:11][C:10]1=[O:29]>C(Cl)Cl>[CH3:8][C:9]1([CH3:30])[CH2:15][O:14][C:13]2[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])[CH:18]=[N:19][C:12]=2[NH:11][C:10]1=[O:29]
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)OCC(C)(C)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)COc2cc(/C=C/C(=O)O)cnc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
TFA (3 mL) was added to a cooled solution of (E)-tert-butyl 3-(3,3-dimethyl-4-oxo-2,3,4,5-tetrahydropyrido[3,2-b][1,4]oxazepin-8-yl)acrylate (1 g, 3 mmol) in CH2Cl2 (5 mL) and stirred for 30 min at rt. The mixture was evaporated and HCl/dioxane (4M, 5 mL) was added. The precipitate that formed was washed with ether and dried to afford the title compound (530 mg, 66%). 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.28 (s, 1H), 7.82 (d, J=15.5 Hz, 1H), 6.84 (d, J=20 Hz, 1H), 4.05 (s, 2H), 1.47 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Li+].CC([N-]C(C)C)C.CN([CH:25]=[O:26])C>C1COCC1>[Cl:1][C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([F:13])[C:10]([CH:25]=[O:26])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1c(F)cccc1Cl
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(C=O)c1F
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a cold solution of ethyl 2-chloro-6-fluorobenzoate (0.500 g, 24.7 mmol) in THF (35 mL) was added LDA (6.6 g, 61.8 mmol) at −78° C. The reaction mixture was stirred for 2 h at same temperature, followed by addition of DMF (2.7 g, 37 mmol). The reaction mixture was further stirred for 2 h at same temperature. The reaction mass was quenched in dilute HCl, extracted with ethyl acetate and concentrated to afford crude product which was further purified by column chromatography eluting with EtOAC: pet.ether to afford 2.00 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 1.31 (t, 3H), 4.42 (q, 2H), 7.94-7.99 (m, 2H), 10.14 (s, 1H).
Reaction SMILES: C(OC([NH:8][N:9]=[C:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=O)(C)(C)C.C([BH3-])#N.[Na+].[ClH:20]>O1CCCC1.CO>[ClH:20].[O:13]1[CH2:14][CH2:15][CH:10]([NH:9][NH2:8])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NN=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NNC1CCOCC1
Temperature: 25 °C
Yield: 60 %

Procedure:
N′-(Tetrahydro-pyran-4-ylidene)-hydrazinecarboxylic acid tert-butyl ester (5.210 g, 24.32 mmol) was dissolved in a mixture of dry tetrahydrofuran (22 mL) and dry methanol (30 mL). Sodium cyanoborohydride was added to the solution resulting in effervescence. When the effervescence subsided, the mixture was heated to reflux for 5-10 minutes. After cooling to room temperature 6N HCl (10.5 mL) was slowly added and then the mixture was heated to reflux for 20 minutes. After cooling to room temperature, the solvent was removed in vacuo. The residue was triturated with hot isopropanol and then cooled to room temperature, diluted with ether and chilled. The solid was collected by filtration and was found to be the reduced material but not completely deprotected. The solid was dissolved in the same THF-methanol mixture and treated with 6N HCl (10.5 mL) at reflux for another 1.5 hours. After cooling to room temperature, the reaction mixture was filtered to remove a small amount of insoluble material. The filtrate was then concentrated in vacuo. Isopropanol was added to the residue and solid quickly began to crystallize out of solution. After chilling overnight, ether was added followed by additional chilling. The solid was then collected by filtration, washed with ether and dried in vacuo to give (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (2.22 g, 60%).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:18][CH:19]1[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1>>[CH2:25]([N:21]1[CH2:22][CH2:23][O:24][CH:19]([CH2:18][N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:16])[CH2:20]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: O=c1[nH]c2ccccc2n1-c1ccccc1
Product: O=c1n(CC2CN(Cc3ccccc3)CCO2)c2ccccc2n1-c1ccccc1

Procedure:
The condensation of 0.1 mol of 1-phenyl-2,3-dihydro-benzimidazol-2-one and 0.1 mol of 2-chloromethyl-4-benzyl-morpholine in accordance with the procedure (a) of Example 1 gives, after evaporation of the solvent under reduced pressure, a pale pink solid which melts at about 90° C. and which is used as such for the subsequent operations.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH2:30])=[CH:28][C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][C:8]3[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCc1ccc2c(c1)OCO2
Product: CCCCN1C(=O)C(NCc2ccc3c(c2)OCO3)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-(1,3-benzodioxol-5-yl)methanamine in a similar manner as described for e.g. Example 6 and 7. 1H NMR (500 MHz, CD3CN): δ 0.97 (t, 3H), 1.39-1.48 (m, 2H), 1.72-1.80 (m, 2H), 3.67 (t, 2H), 4.05 (d, 2H), 5.91 (s, 2H), 6.26-6.34 (m, 2H), 6.64 (d, 1H), 7.32-7.48 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2S)[CH:5]=[CH:6][CH:7]=1.OO>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn(-c2cccc(Br)c2)c(S)n1
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cn(-c2cccc(Br)c2)cn1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.31) (400 mg, 1.09 mmol) and 4-methyl-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole [in situ prepared by the following sequence: Step 1) A mixture of commercially available 3-bromophenylisothiocyanate (10.06 g, 47.0 mmol) and 2-aminopropionaldehyde dimethylacetal (5.96 mL, 47.0 mmol) in EtOH (50 mL) was refluxed for 1 h. Evaporated to dryness to give 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methylethyl)-thiourea as an off-white solid (15.69 g, 100%). Step 2) A mixture of the above prepared 1-(3-bromo-phenyl)-3-(2,2-dimethoxy-1-methyl-ethyl)-thiourea (15.69 g, 47 mmol) in H2O (85 mL) and 37% HCl (8.5 mL) was refluxed for 4.5 h. Removed from oilbath, added ice and ice water (total volume: 250 mL), the precipitate was filtered off, washed several times with ice water and dried in vacuum at 60° C. to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole-2-thiol as a light orange solid (8.71 g, 69%). Step 3) To a suspension of the above prepared 1-(3-bromophenyl)-4-methyl-1H-imidazole-2-thiol (6.00 g, 22 mmol) in acetic acid (20 mL) and water (5 mL) was added dropwise 35% H2O2 (13.4 mL, 156 mmol) within 15 min keeping the internal temperature below 60° C. Stirred at 23° C. for 30 min, poured onto ice, destroyed excess H2O2 by addition of sat. Na2SO3-sol., adjusted pH with 32% NaOH-sol. until pH 9 is reached, extracted with EtOAc (3×100 mL), the combined organic layers were washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a red oil, which was purified by silica gel column chromatography with EtOAc to give the 1-(3-bromo-phenyl)-4-methyl-1H-imidazole as a brown oil (3.80 g, 72%). Step 4) A mixture of the above prepared 1-(3-bromo-phenyl)-4-methyl-1H-imidazole (0.313 g, 1.31 mmol), bis(pinacolato)diboron (0.364 g, 1.438 mmol), potassium acetate (0.389 g, 3.96 mmol) and PdCl2(PPh3)2 (0.023 g, 3 mol %) in DMF at 100° C. for 2 h; then addition of Pd(OAc)2 (0.007 g, 3 mol %) and dppf (0.018 g, 3 mol %) and stirred at 100° C. overnight. This solution obtained was used directly.] according to the general procedure VI. Obtained as an off-white solid (0.140 g, 32%). MS (ISP) 394.0 [(M+H)+]; mp 126-132° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH2:20][CH2:19]2)[C:11]1=[O:21].Cl>CN(C)C=O>[O:8]=[C:5]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][C:11](=[O:21])[C:12]12[CH2:20][CH2:19]1)[CH2:6][CH3:7]
Reactant: O=C1Nc2ccccc2C12CC2
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC(=O)c1ccc2c(c1)C1(CC1)C(=O)N2
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A slurry was made from 7.5 ml of dimethylformamide and 45.5 g of anhydrous aluminum chloride. The temperature rose to 40° C. and 2.97 ml of propionyl chloride and 5.43 g of spiro[cyclopropane-1,3'-[3H]-indol]-2'(1'H)-one were added. The mixture was stirred for 2 hours at 70° C. and was slowly poured into a mixture of ice and 50 ml of concentrated hydrochloric acid. After cooling overnight, the resulting precipitate was recovered by filtration. Crystallization from ethyl acetate provided 4.9 grams of the desired subtitle intermediate, m.p. 183°-185° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5]1)([CH3:3])[CH3:2].[C:16]1([OH:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CCOCC>[C:16]1([O:26][CH2:5][CH:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)N1CC(OCc2ccccc2)C1
Reactant: Oc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)NCC(COc1cccc2ccccc12)OCc1ccccc1
Temperature: 200 °C
Yield: 79 %

Procedure:
To a mixture of 6.2 parts of 1-(iso-propyl)-3-benzyloxyazetidine and 43 parts of α-naphthol 1.5 parts of sodium hydroxide was added, and the mixture was heated at 200° C. for 16 hours. The reaction mixture was cooled, and 100 parts of ether were added thereto. Excessive α-naphthol was removed by extraction with 2N-sodium hydroxide aqueous solution. The remaining ether layr was washed in water and dried over anhydrous sodium sulfate. After distillation of ether, the residue was subjected to distillation to yield 8.3 parts of 1-(α-naphthoxy)-2-benzyloxy-3-(iso-propylamino)-propane boiling at 192°-195° C. The yield was 79%.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH2:13]([N:16]=[C:17]=[O:18])[CH2:14][CH3:15]>C(OCC)C>[CH2:13]([NH:16][C:17](=[O:18])[O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:14][CH3:15]
Reactant: CCCN=C=O
Reactant: CCCCCCCCCCCO
Solvent: CCOCC
Product: CCCCCCCCCCCOC(=O)NCCC
Yield: 89 %

Procedure:
For example, 8.6 g (50 mmol) of 1-undecanol, 5 ml (1.07 eq.) n-propyl isocyanate and 50 ml diethyl ether were heated in a stainless steel bomb at 65° for 72 hours. Solvent and excess isocyanate were removed on a rotary evaporator and the residue was crystallized from hexane to give 11.5 g (89%) of 1-undecyl propylcarbamate, mp 45°-45.5°.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[OH:11][CH:12]1[CH2:15][NH:14][CH2:13]1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:19]=1[C:20]#[N:21]>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:18]([CH2:17][N:14]2[CH2:15][CH:12]([OH:11])[CH2:13]2)=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: OC1CNC1
Reactant: N#Cc1cc(Cl)ccc1CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1CN1CC(O)C1
Yield: 82.3 %

Procedure:
DIEA (3.57 mL, 20.50 mmol) was added to a stirred mixture of 3-hydroxyazetidine hydrochloride (1.00 g, 9.11 mmol) and 2-bromomethyl-5-chlorobenzonitrile (2.10 g, 9.11 mmol) in CH2Cl2 (75 mL). After 16 h the reaction mixture was concentrated and the residue was partitioned between ether and 1N HCl. The aqueous layer was washed with ether, made neutral with NaHCO3, saturated with NaCl and extracted into CH2Cl2. The organic layer was dried (Na2SO4) and evaporated to give 5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzonitrile (1.67 g) as a gum: 1H NMR (CDCl3, 400 MHz) δ 3.03 (m, 2H), 3.68 (m, 2H), 4.49 (t, J=6.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.53 (d,d, J=2.2, 6.2 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H).
Reaction SMILES: C(OC1C=C(F)C=C2C=1C(CC(N1CC3C(=CC=CC=3)C1)=O)=C[N:13]2CC)C1C=CC=CC=1.[CH2:33]([N:36]1[C:44]2[C:39](=[C:40]3[O:48][CH2:47][CH2:46][O:45][C:41]3=[CH:42][CH:43]=2)[C:38]([CH2:49][C:50]([OH:52])=O)=[CH:37]1)[CH2:34][CH3:35]>>[CH2:33]([N:36]1[C:44]2[C:39](=[C:40]3[O:48][CH2:47][CH2:46][O:45][C:41]3=[CH:42][CH:43]=2)[C:38]([CH2:49][C:50]([NH2:13])=[O:52])=[CH:37]1)[CH2:34][CH3:35]
Reactant: CCn1cc(CC(=O)N2Cc3ccccc3C2)c2c(OCc3ccccc3)cc(F)cc21
Reactant: CCCn1cc(CC(=O)O)c2c3c(ccc21)OCCO3
Product: CCCn1cc(CC(N)=O)c2c3c(ccc21)OCCO3
Yield: 100 %

Procedure:
Following the procedure (step 1, scheme 31) used to prepare compound 31-2, compound 40-5 gave compound 40-6 in 100% yield as yellow oil. LCMS: calc 274.1 found 275.0 [MH]+.