Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4].[NH2:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([Cl:23])[N:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C)=O>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C:20]3[CH:19]=[C:18]([Cl:23])[N:17]=[C:16]([NH2:15])[N:21]=3)=[CH:13][C:8]=2[O:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1coc2cc(O)ccc12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1coc2cc(Oc3cc(Cl)nc(N)n3)ccc12
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
A mixture of 6.20 g (32.3 mMol) 6-hydroxy-benzofuran-3-carboxylic acid methyl ester, 8.5 g (51.8 mMol) 2-amino-4,6-dichloropyrimidine and 14.2 g (67 mMol) K3PO4 in 250 ml NMP is stirred for 3.5 h at 60° C. Then the mixture is poured into 1 l EtOAc and 1 l water, the aq. layer separated off and extracted 3 times with EtOAc. The organic phases are washed with water and brine and dried (Na2SO4). Then char coal is added, the mixture filtered and the filtrate concentrated. Trituration from ether gives the title compound: m.p.: 213-214° C. More product can be obtained from the filtrate by column chromatography (SiO2; hexane/EtOAc 2:1) as described in step 9.4.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])[C:16](=[O:29])[C:15]=1[Cl:30].CN1CCOCC1.[CH2:43]([O:45][C:46](Cl)=[O:47])[CH3:44]>CC(N(C)C)=O>[Cl:30][C:15]1[C:16](=[O:29])[N:17]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])[C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][C:11]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:10]=1[CH2:9][NH:8][C:46](=[O:47])[O:45][CH2:43][CH3:44]
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(OCc2ccc(F)cc2CN)c(Cl)c(=O)n1-c1c(F)cccc1F
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Product: CCOC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one trifluoroacetate (0.3 g, 0.00057 mol) in dimethylacetamide (3.0 mL) was added N-methymorpholine (0.064 g, 0.00064 mol), followed by addition of ethylchloroformate (0.06 mL) and stirred at −10° C., for 30 min. The solvents were distilled in vacuo and the residue was purified by reverse-phase HPLC purification using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z=481 M+H) were combined and freeze-dried, and the residue was partitioned between 5% sod. bicarbonate (20 mL) and dichloromethane (20 mL). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure, to afford the title compound as a white amorphous powder (0.15 g, 55%): 1H NMR (CD3OD/400 MHz) δ 7.61 (m, 1H), 7.52 (m, 1H), 7.26 (˜t, 2H, J=8.4 Hz), 7.12 (dd, 1H), 7.05 (3d, 1H, J=2.4 Hz), 6.74 (s, 1H), 5.40 (s, 2H), 4.42 (s, 2H), 4.05 (q, 2H, J=7.2 Hz), 2.12 (s, 3H), and 1.21 (t, 3H, J=7.2 Hz); ES-HRMS m/z 481.1118 (M+H C23H21N2O4F3Cl requires 481.1136).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[F:10][CH:11]([F:21])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][NH:16]1)=[O:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[F:21][CH:11]([F:10])[C:12]([N:14]=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]1[CH2:2][C:3]1[CH:8]=[N:7][C:6]([F:9])=[CH:5][CH:4]=1)=[O:13]
Reactant: O=C(N=c1cccc[nH]1)C(F)F
Reactant: Fc1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N=c1ccccn1Cc1ccc(F)nc1)C(F)F
Temperature: 65 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
128 mg (0.75 mmol) of 5-bromomethyl-2-fluoropyridine was dissolved in 3 ml of anhydrous DMF, 116 mg (0.68 mmol) of 2,2-difluoro-N-[pyridin-2(1H)-ylidene]acetamide was dissolved in 3 ml of anhydrous DMF and added thereto, and subsequently, 103 mg (0.75 mmol) of potassium carbonate was added thereto and the resulting mixture was stirred at 65° C. for 2 hours. After the reaction was completed, the reaction solution was returned to room temperature, and ethyl acetate and water were added thereto to perform liquid separation. The organic layer was washed with 1% hydrochloric acid, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A small amount of hexane and diethyl ether were added thereto to precipitate crystals, and thus the crystals were collected and dried to obtain the subject material. Amount obtained 50 mg (yield 26%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([OH:17])=O)[C:11]=2[CH3:18])=[CH:6][CH2:5]1)([CH3:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[C:32](=[O:44])[N:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[N:34]([CH3:37])[C:35]=1[CH3:36].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O.O>[CH:38]1([N:33]2[C:32](=[O:44])[C:31]([NH:30][C:15]([C:12]3[C:11]([CH3:18])=[C:10]([C:7]4[CH2:8][CH2:9][CH:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH:6]=4)[O:14][N:13]=3)=[O:17])=[C:35]([CH3:36])[N:34]2[CH3:37])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)noc1C1=CCC(C(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1=CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [5-(4-isopropylcyclohex-1-en-1-yl)-4-methylisoxazole-3-carboxylic acid] (42 mg, 0.168 mmol) in dry DCM (3 mL) under nitrogen was added DMF (0.026 mL, 0.337 mmol) followed by oxalyl chloride (0.016 mL, 0.185 mmol) and the mixture was stirred at room temperature for 30 mins. 4-Amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (38.8 mg, 0.185 mmol) was added followed by triethylamine (0.070 mL, 0.505 mmol) and the mixture was stirred for 30 mins. Water was added and the mixture was stirred vigorously before passing through a phase separating cartridge. The organic eluent was collected and concentrated under reduced pressure to give an orange oil. The crude material was dissolved in DMSO (0.9 mL) and purified using mass-directed automated reverse phase chromatography over a 9.5 minute gradient of 50-98% MeCN in water (0.1% formic acid). The product fraction was concentrated under reduced pressure. The remaining aqueous was treated with a saturated aqueous solution of sodium hydrogen carbonate and extracted with DCM, passing the organic extracts through a phase separating cartridge. The solvent was removed under a stream of air and dried under reduced pressure to afford the title compound;
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].C(Cl)Cl.[NH2:40][OH:41].[OH-].[Na+]>CO.O>[OH:41][NH:40][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:7][CH:6]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(CN6CCN(C)CC6)o5)cc4c3C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3ccc4[nH]c5c(c4c3)CN(c3ncc(C(=O)NO)cn3)CC5)o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methyl-2-{8-[5-((4-methylpiperazin-1-yl)methyl)-2-furyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.1 g) in methanol:DCM (5:2 mL) was added 50% aqueous hydroxylamine solution (2 mL) and to the mixture was added solution of NaOH (0.8 g) in water (0.5 mL). The reaction mixture was stirred at room temperature for 1 hr and the progress of the reaction was monitored by TLC and upon completion of the reaction the solvent was removed under reduced pressure. The pH of the mixture was adjusted to 7.5 using 1N HCl and the obtained solid was filtered and washed with water followed by diethyl ether and dried under vacuum to give Example 108 (0.08, 64.87%). HPLC: (Rt=11.58); m/e=488 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][N:24]=2)[CH2:19][C:18]1=[O:26]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:19]1[C:20]2[C:25](=[N:24][CH:23]=[CH:22][CH:21]=2)[NH:17][C:18]1=[O:26])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2cccnc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3ncccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was methylated and then formylated. The aldehyde was condensed with 7-aza-2-oxindole to give 0.2 g of 3-(3,5-diisopropyl-4-methoxybenzylidene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30]O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:43]1[CH:48]=[CH:47][CH:46]=CC=1>>[N:43]1([CH2:30][C@@H:28]2[CH2:29][C@H:26]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH:12]=4)=[C:9]3[CH3:25])[CH2:27]2)[CH2:46][CH2:47][CH2:48]1
Reactant: c1ccncc1
Reactant: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC2)C1

Procedure:
The title compound is prepared in analogy to Example 116 starting from 0.35 g (0.84 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol and 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml dry pyridine, followed by 0.442 ml (6.33 mmol) trimethylenimine (Fluka, Buchs, Switzerland). Analytical HPLC: tR=9.22 min (Grad 1); ES-MS: m/eo=454.3; NMR (DMSO-d6): 8.08/s (1H), 7.25-7.5/several m's (6H), 7.02/“d” (1H); 6.93/s (1H); 6.89/“d” (1H); 5.4-6.0/b (NH2); 5.13/s (2H); 4.76/m (1H); 3.11/“t” (4H); 2.75-2.90/m (2H); 2.54/d (2H); 2.35-2.45/m (2H); 2.22/s (3H); 2.03/m (1H); 1.9-2.0/m (2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([NH2:16])=[CH:4][CH:3]=1.[CH:17](O)=O>>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:17]=[N:16][C:5]2=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Nc1ccc(Cl)nc1NCC1CCOCC1
Product: Clc1ccc2ncn(CC3CCOCC3)c2n1

Procedure:
A solution of the crude product of Example 7B (0.979 g, 4.05 mmol) in formic acid (2 mL, 52.1 mmol) was heated at 95° C. for 1 hour. After cooling, the mixture was concentrated and dissolved in ethyl acetate. The mixture was washed with dilute potassium carbonate and brine, dried over magnesium sulfate, filtered and concentrated. Recrystallization from ethyl acetate/hexane afforded the title compound. MS (ESI) m/z 252 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[Cl:19][CH2:20][S:21](Cl)(=[O:23])=[O:22]>>[Cl:19][CH2:20][S:21]([NH:18][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[C:6]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=1[F:17])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)CCl
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Product: O=S(=O)(CCl)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with chloromethanesulfonyl chloride to obtain the desired product, m/z=475 [M−1]−.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([SH:22])[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:23][C:24]1[N:33]=[C:32](Cl)[C:31]2[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:35][CH3:36])[CH:30]=2)[N:25]=1>CN(C=O)C.O>[C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][C:32]3[C:31]4[C:26](=[CH:27][C:28]([O:37][CH3:38])=[C:29]([O:35][CH3:36])[CH:30]=4)[N:25]=[C:24]([Cl:23])[N:33]=3)[CH:17]=2)=[O:14])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nc(Cl)nc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC
Temperature: 25 °C
Yield: 13 %

Procedure:
To a slurry of sodium hydride (7.5 mg, 0.3 mmol) in DMF (3 mL) was added 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (90 mg, 0.3 mmol), and the solution stirred at room temperature When gas evolution ceased, 2,4-dichloro-6,7-dimethoxyquinazoline (78 mg, 0.3 mmol) was added and the solution heated at 50° C. overnight, cooled to room temperature, and diluted with H2O. The mixture was extracted with EtOAc, the organic layer washed with aqueous sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude solid was purified by HPLC to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(2-chloro-6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (20 mg, 0.04 mmol, 13%). 1H NMR (300 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.53 (s, 1H), 7.90 (s, 1H), 7.62 (d, 1H), 7.44 (t, 1H), 7.36 (s, 2H), 7.27 (d, 1H), 6.49 (s, 1H), 4.00 (s, 6H), 1.28 (s, 9H); LC-MS (ESI) m/z 514 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][CH:11]([OH:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>>[I:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH:11]2[O:21][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=[N+]([O-])c1cn(CC(O)COc2ccc(I)cc2)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cn2c(n1)OC(COc1ccc(I)cc1)C2
Reaction time: 1 h
Yield: 77 %

Procedure:
Ring closure of alcohol 84 with NaH as in Example 2A at 0° C. for 80 min and then at 17° C. for 60 min, followed by chromatography of the product on silica gel, eluting with 0-40% EtOAc/petroleum ether (foreruns) and then with 40% EtOAc/petroleum ether and 0-0.5% MeOH/CH2Cl2, gave 2-[(4-iodophenoxy)methyl]-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (85) (77%) as a pale yellow solid: mp (MeOH/CH2Cl2/hexane) 198-199° C.; 1H NMR [(CD3)2SO] δ 8.15 (s, 1H), 7.61 (dt, J=8.9, 2.6 Hz, 2H), 6.80 (dt, J=9.0, 2.6 Hz, 2H), 5.72 (m, 1H), 4.49 (dd, J=10.7, 9.0 Hz, 1H), 4.41 (dd, J=11.6, 2.7 Hz, 1H), 4.35 (dd, J=11.6, 5.2 Hz, 1H), 4.20 (dd, J=10.8, 6.5 Hz, 1H). Anal. (C12H10IN3O4) C, H, N.
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[CH3:11].COCC(OC)=O.[Cl:19]CCl>COC(C)(C)C>[ClH:19].[NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[CH3:11]
Reactant: ClCCl
Agent: COCC(=O)OC
Agent: C[C@@H]1Cc2ccccc2[C@H]1N
Solvent: COC(C)(C)C
Product: Cl
Reaction time: 2 h

Procedure:
Novozym 435 (Aldrich Corp., 1.0 g) was added to a mixture of trans-1-amino-2-methylindane (6.6 g, 0.0448) and methyl 2-methoxyacetate (5.04 g 0.0484 mol) in tert-butyl methyl ether. The mixture was heated at reflux for 2 hours, a further amount of Novozym 435 (0.5 g) added and heating is continued for an additional 2 hours. Dichloromethane was added to the cooled mixture and the biocatalyst filtered off. The organic layer was dried (sodium sulfate), evaporated and the residue dissolved in the minimum of dichloromethane. A solution of ethanolic hydrochloric acid (8N) was added and the solid filtered to give (1S,2R)-1-amino-2-methylindane hydrochloride, and the filtrate evaporated to give N-[(1R,2S)-2-methyl-1-indanyl]-2-methoxyacetamide (5.9 g), m.p. 78-79° C.
Reaction SMILES: C1(N)CCCCC1.[N+](C1C=CC(OC(N[C@@H](CC2C=CC=CC=2)C(=O)CN(C)C(N2CCC[C@H]2C(OCC2C=CC=CC=2)=O)=O)=O)=CC=1)([O-])=O.[CH:51]1([NH:57][C:58]([NH:60][C@@H:61]([CH2:84][C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[C:62](=[O:83])[CH2:63][N:64]([CH3:82])[C:65]([N:67]2[CH2:81][CH2:80][CH2:79][C@H:68]2[C:69]([O:71]CC2C=CC=CC=2)=[O:70])=[O:66])=[O:59])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1>C1(C)C=CC=CC=1>[CH:51]1([NH:57][C:58]([NH:60][C@@H:61]([CH2:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)[C:62](=[O:83])[CH2:63][N:64]([CH3:82])[C:65]([N:67]2[CH2:81][CH2:80][CH2:79][C@H:68]2[C:69]([OH:71])=[O:70])=[O:66])=[O:59])[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]1
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)NC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: NC1CCCCC1
Solvent: Cc1ccccc1
Product: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)NC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Cyclohexylamine (1 ml., 8.7 ml., 8.7 mmole) is added to a cold (0°) solution of 1-[[[(S)-3-[[(4-nitrophenoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester (0.9 g., 1.58 mmole) in toluene in one portion. The solution turns yellow immediately and TLC indicates all starting material has been consumed. The resulting solution is washed sequentially with water, 1N hydrochloric acid, and 10% sodium bicarbonate. The organic layer is dried (MgSO4) and concentrated to a pale yellow oil. The crude product is purified (2x) by preparative layer chromatography using ethyl acetate as eluant to give 0.31 g. of 1-[[[(S)-3-[[(cyclohexylamino)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester as a clear, colorless salt.
Reaction SMILES: B#B.[CH3:3][CH:4]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH:5]=[CH2:6].[Br:15]Br.C[O-].[Na+]>O1CCCC1.CO.O>[Br:15][CH2:6][CH2:5][CH:4]([CH3:3])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: BrBr
Reactant: C=CC(C)COC1CCCCO1
Agent: B#B
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(CCBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65741.3 %

Procedure:
Diborane in tetrahydrofuran (125 ml, 0.150 m) at 0° C. under nitrogen is added to a mixture of 3-methyl-4-(tetrahydropyran-2-yloxy)-1-butene (72 g, 0.423 m) and tetrahydrofuran (150 ml). After the addition is complete, the mixture is allowed to warm to room temperature and then stirred for 1 hour. The reaction mixture is cooled to 0° and bromine (24 ml, 0.43 mmole) and sodium methoxide (0.565 m) in methanol (300 ml) are added slowly simultaneously. After the addition is complete, the mixture is allowed to warm to room temperature and stirred for 30 minutes. The mixture is then treated with water (100 ml) and extracted with petroleum ether (2×200 ml). The organic layer is washed with 5% sodium bicarbonate (100 ml), water (2×100 ml) and dried (Na2SO4). The solvent is removed in vacuo to give a colorless liquid. This crude product is purified by column chromatography on silica gel (500 g, 1% ether in petroleum ether) to give 1-bromo-3-methyl-4-(tetrahydropyran-2-yloxy)-butane (71 g, 65%) as a colorless liquid.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH2:20][C@H:19]([O:24]C(=O)C(C)(C)C)[CH2:18][CH2:17]2)C.Cl[CH2:41][C:42]([N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])=O>>[CH2:45]([N:44]([CH2:47][CH3:48])[CH2:42][CH2:41][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[C@@H:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH3:46]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1-c1ccc2c(c1)CC[C@@H](OC(=O)C(C)(C)C)C2
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 89.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}tetrahydronaphthalen-2-yl ester (16 mg) and 2-chloro-N,N-diethylacetamide (8.1 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.2 mg) was obtained.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[F:30][C:31]1[CH:39]=[C:38]2[C:34]([C:35]([C:40]3[CH2:41][CH2:42][NH:43][CH2:44][CH:45]=3)=[CH:36][NH:37]2)=[CH:33][CH:32]=1>CS(C)=O.C(OCC)(=O)C>[F:30][C:31]1[CH:39]=[C:38]2[C:34]([C:35]([C:40]3[CH2:41][CH2:42][N:43]([CH2:12][CH:13]4[O:22][C:21]5[C:16](=[CH:17][CH:18]=[C:19]6[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]6=5)[O:15][CH2:14]4)[CH2:44][CH:45]=3)=[CH:36][NH:37]2)=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(C3=CCN(CC4COc5ccc6[nH]c(C(F)(F)F)nc6c5O4)CC3)c[nH]c2c1
Temperature: 85 °C

Procedure:
A mixture of 0.50 g (1.2 mmole) of [(8R)-2-trifluoromethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 0.90 g (4.2 mmole) of 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 8.0 mL of DMSO was heated at 85° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 400 mL with ethyl acetate, washed with 400 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and recrystallized from ethanol with the addition of 0.10 g of fumaric acid to give 0.16 g of the (S)-enantiomer of the title compound as a yellow solid hemifumarate, hydrate, m.p. 215-220° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][S:12][CH2:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([CH2:30][CH3:31])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:15])=[CH:5][CH:4]=1)#[N:2].C(#N)C.I([O-])(=O)(=O)=[O:37].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[CH2:11][S:12]([CH2:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[N:21]([CH2:30][CH3:31])[C:22]4[C:27]([C:28]=3[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:15])=[O:37])=[CH:5][CH:4]=1)#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CSCC(=O)Nc3ccc(C#N)cc3)ccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCn1c2ccccc2c2cc(NC(=O)CS(=O)CC(=O)Nc3ccc(C#N)cc3)ccc21
Temperature: 25 °C
Reaction time: 432 h
Yield: 23.3 %

Procedure:
To a solution of 2-({2-[(4-cyanophenyl)amino]-2-oxoethyl}sulfanyl)-N-(9-ethyl-9H-carbazol-3-yl)acetamide (55 mg, 0.12 mmol) in a mixed solvent of acetonitrile (4 mL) and water (2 mL) was added sodium periodate (29.2 mg, 0.14 mmol), and the mixture was stirred at room temperature for 18 days. Aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate solution, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (13 mg, 0.028 mmol, 23%) as a pale-yellow powder.