Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2([N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:20])[CH2:18][CH2:17]2)[CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:24]([O:23][C:21]([N:19]([C:16]1([C@@H:13]2[CH2:14][CH2:15][NH:11][CH2:12]2)[CH2:18][CH2:17]1)[CH3:20])=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-benzyloxycarbonyl-3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (1.31 g, 3.48 mmol) was dissolved in ethanol (13 ml), and after adding a 10% palladium carbon catalyst (water content: 50%; 0.65 g) thereto, it was stirred at room temperature for 5 hours under a hydrogen atmosphere at atmospheric pressure. After performing filtration through cellite (ethanol washing), the filtrate was concentrated under a reduced pressure. As a result, 0.92 g (quantitative) of the title compound was obtained in the form of a colorless syrup.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C@H:26]2[OH:38])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][C:26]2=[O:38])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(OCc3ccccc3)cc2)[C@H](O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
To a solution of DMSO (3.7 mL, 52 mmol) in 50 mL of DCM under nitrogen at −78° C. was added oxalyl chloride (4.45 mL, 51 mmol). The mixture was stirred for 10 minutes after the completion of the addition. Then a solution of (±)-rel-(3S,4S)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (from Example 50, step D, 6.5 g, 17 mmol) in 50 mL of DCM was added and the mixture was stirred in the cold for a further 90 minutes. The reaction was then quenched by the addition of 11.8 mL of triethylamine (85 mmol) and allowed to warm up to rt. The mixture was then partitioned between 200 mL brine and 200 mL DCM. The layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was subjected to column chromatography on 48 g of basic alumina eluting with 8% ethyl acetate/hexanes to afford 4.7 g (67%) of racemic tert-butyl 4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate. LCMS (method F) RT 2.376 min, m/z 381.2 (M+); chiral SFC (method G) RT 4.54 min (46.9% AP, 4.93 min (49.7% AP). 1H NMR (400 MHz, DMSO-d6) δ 7.30-7.40 (m, 5H), 7.07 (d, J=7 Hz, 2H) 6.94 (d, J=7), 2H; 5.08 (s, 2H), 4.10 (d, J=17.6, 1H), 3.97 (d, J=17.6, 1H), 3.77 (m, 2H), 3.43 (br s, 1H), 2.16 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[S:12])=[C:30]([CH3:35])[CH:29]=1
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 56%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:25][C:26](Cl)=[O:27])[CH2:23][CH3:24]>C1C=CC=CC=1>[C:26](=[O:27])([O:25][CH2:22][CH2:23][CH3:24])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.390 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 4.0 ml. of absolute pyridine and reacted with 0.293 g. of chloroformic acid n-propyl ester as in Example 1. The 0.546 g. of brownish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.528 g. of yellowish crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-propyl carbonate obtained melts at 70.2°-70.9° and is liquid crystalline (monotrope) upon cooling to 68.2°. UV (EtOH): ε270 = 26,000.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28]([OH:37])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[C:10]([C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][NH:15][CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].CCOCC.CCCCCC>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][C:28]([OH:37])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH:10]([C:12]2[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:14][NH:15][CH:16]=2)[OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(c1c[nH]nc1-c1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CCCCCC
Product: OC(c1c[nH]nc1-c1ccccc1)C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of 4-[2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-3-phenyl-1H-pyrazole (95 mg), prepared as described in Example 3, in methanol (3 mL) was cooled to 0° C. and treated with sodium borohydride (9 mg). The mixture was allowed to warm to room temperature and was stirred for 1 hour. The solvent was evaporated and the residue partitioned between water and ethyl acetate. The organic extracts were washed (water, brine) combined, dried, and evaporated to afford a white foam. Trituration with ether:hexane (1:2) afforded the title compound as a white solid (62 mg); mp 133°-135° C.; NMR: 7.57-7.23 (m,13), 7.03 (m,1), 5.11 (d,1), 3.04 (m,1), 2.86 (m,2), 2.51 (m,2), 2.37 (m,2), 2.23 (m,2), 1.94 (m,1), 1.81-1.60 (m,3); MS: m/z=536(M+1). Analysis for C30H31Cl2N3O2 ·1.00 H2O: Calculated: C, 64.98; H, 5.82; N, 7.83; Found: C, 64.91; H, 5.74; N, 7.53.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=2)=[N:6][N:7](C2(CC#N)CCN(C(OC(C)(C)C)=O)CC2)[CH:8]=1)(=[O:3])[NH2:2].CC([O-])(C)C.[K+]>C1COCC1.[NH4+].[Cl-]>[C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:30][CH:31]=2)=[N:6][NH:7][CH:8]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)Cc1ccc(Nc2nn(C3(CC#N)CCN(C(=O)OC(C)(C)C)CC3)cc2C(N)=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(Nc2n[nH]cc2C(N)=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-Butyl 4-(4-carbamoyl-3-{[4-(2-methoxy-2-oxoethyl)phenyl]amino}-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (226 mg, 0.46 mmol) in THF (2.3 mL) at 0° C. was added KOtBu (0.68 mL, 0.68 mmol, 1.0M in THF), and the mixture was stirred at 0° C. for 20 minutes, then ambient temperature for 20 minutes. The mixture was diluted with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. Et2O (5 mL) was added to the resulting oily residue and a solid precipitated out. This solid was collected by decant, and washed with Et2O to afford the title compound. LRMS (ESI) calc'd for C13H15N4O3 [M+H]+: 275. Found: 275.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]([OH:15])=O)[S:10][C:6]=2[CH:5]=1)[CH3:2].[CH2:18]([NH2:21])[CH2:19][CH3:20].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]([NH:21][CH2:18][CH2:19][CH3:20])=[O:15])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(SCC(=O)O)sc2c1
Reactant: CCCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)CSc1nc2ccc(OCC)cc2s1
Reaction time: 20 h
Yield: 45.5 %

Procedure:
To a stirred solution of 24 (110.3 mg, 0.41 mmol) and n-propylamine (50.5 mg, 0.50 mmol) in CHCl3 (2.0 ml), HOBt (190 mg, 1.41 mmol) and EDC (120 mg, 0.63 mmol) were added at room temperature. After stirring for 20 hours, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by HPLC (gradient from 20%, acetonitrile 80% in DDW to 100% acetonitrile, in 15 minutes) to give 33 (57.9 mg, 36% yield) as a brown amorphous solid, range of m.p. temperature was too large for a clear determination. 1H NMR (DMSO-d6): δ 0.97 (t, 3H, J=6.8), δ 1.27 (t, 3H, J=7.1), δ 1.53 (m, 2H, J=6.8, 3.5), δ 3.54 (d, 2H, J=3.7), δ 4.01 (s, 2H), δ 4.19 (q, 2H, J=7.3), δ 6.23 (amide broad peak), δ 6.97 (dd, 1H, J=10.8, J=3.7), 7.33 (d, 2H, J=8.8). 13C NMR (DMSO-d6): δ 12.8, 13.76, 20.6, 39.56, 40.78, 65.1, 101.79, 114.78, 123.6, 135.79, 145.8, 154.67, 168.4, 169.95. MS: MW=310.07 g/mol, MNa+=333.18 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH3:21])([CH3:20])[CH2:15][CH2:14][C:13]3([CH3:23])[CH3:22])[C:7]=1[O:8][CH3:9].CN(C)[CH:28]=[O:29]>C1COCC1>[CH3:21][C:16]1([CH3:20])[CH2:15][CH2:14][C:13]([CH3:23])([CH3:22])[C:12]2[CH:11]=[C:10]([C:6]3[C:7]([O:8][CH3:9])=[C:2]([CH:3]=[CH:4][C:5]=3[O:24][CH3:25])[CH:28]=[O:29])[CH:19]=[CH:18][C:17]1=2
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(OC)c1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 72.2 %

Procedure:
To a solution of 6-(5-bromo-2,6-dimethoxyphenyl)-1,1,4,4-tetramethy-1,2,3,4-tetrahydronaphthlene (0.24 g, 0.55 mmol) in anhydrous THF (6 mL) was added at −78° C. under argon n-BuLi (1.6 M in hexane, 0.7 mL, 1.1 mmol). The solution was stirred for 5 minutes at −78° C. and N,N-dimethylformamide (0.13 mL, 1.65 mmol) was added. The reaction mixture was stirred 2 hours at −78° C. then quenched with aqueous ammonium chloride and brought to room temperature. The solution was diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed and silica gel (eluent: ethyl acetate/hexane, 1:9) to give 0.14 g (72%) of 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-2,4-dimethoxy-benzaldehyde. 1H NMR (500 MHz; CDCl3): δ1.29 (s, 6H); 1.32 (s, 6H); 1.72 (s, 4H); 3.37 (s, 3H); 3.83 (s, 3H); 6.83 (d, J=9.0 Hz, 1H); 7.14 (dd, J1=2.0 Hz, J2=8.5 Hz, 1H); 7.33 (d, J=8.0 Hz, 1H); 7.36 (s, 1H); 7.85 (d, J=8.5 Hz, 1H); 10.29 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[S:25]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26]1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:30]([C:27]3[CH:28]=[CH:29][S:25][CH:26]=3)(=[O:32])=[O:31])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccsc1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccsc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 3-thiophenesulfonyl chloride (47 mg, 0.256 mmol), the title compound was obtained as a white solid (68 mg, 56% yield). MS (ESI): 490.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:12]1(C(OC(C)(C)C)=O)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O)C(N)(CO)CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: NC(CO)(CO)CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reaction time: 3 h
Yield: 109.4 %

Procedure:
3,4-Dichlorophenylisocyanate (3.43 g) and tert-butyl piperazine-1-carboxylate (3.40 g) were stirred for 18 hours in chloroform (20 ml) at room temperature. Trisamine resin (1 g) was added and the mixture stirred for 3 hours, then filtered off. Trifluoroacetic acid (10 ml) was added to the filtrate and this mixture was stirred for two hours. The reaction mixture was concentrated in vacuo and the resulting oil separated between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo to give the title compound (5.47 g).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Mg]Br)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].BrCCCCCCCCO[Si](C(C)(C)C)(C)C.[Mg].BrCCBr.[CH3:41][Si:42]([CH3:51])([CH3:50])[C:43]1[O:47][CH:46]=[C:45]([CH:48]=[O:49])[CH:44]=1>O1CCCC1>[OH:49][CH:48]([C:45]1[CH:44]=[C:43]([Si:42]([CH3:51])([CH3:50])[CH3:41])[O:47][CH:46]=1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCC[Mg]Br
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: CC(C)(C)[Si](C)(C)OCCCCCCCCBr
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C)[Si](C)(C)OCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 8-t-butyldimethylsiloxyoctylmagnesium bromide (5.63 mmol prepared from 1-bromo-8-t-butyldimethylsiloxyoctane 1.82 g, 5.63 mmol and 6.19 mmol magnesium; with a catalytic amount of 1,2-dibromoethane as initiator) in tetrahydrofuran (2 ml) at 0° under argon was added dropwise 5-trimethylsilyl-3-furaldehyde (0.866 g, 5.15 mmol) in tetrahydrofuran (10 ml). The solution was warmed to room temperature, stirred for one hour, quenched with cold 10% hydrochloric acid and extracted into ethyl ether. The organic portion was washed with saturated sodium bicarbonate, water saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a pale oil. Purification by flash chromatography (silica, 5 to 10% ethyl acetate/hexane) gave the desired alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16]CC)=[O:15])=[C:11]([CH3:13])[N:12]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.[OH-].[Na+].Br>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2OC)nc1C
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cl)ccc1-c1nc(C)c(C(=O)O)s1
Yield: 97.3 %

Procedure:
Ethyl 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylate (4.83 g, 15.5 mmol) prepared in the Step 7-1-3 was suspended in ethanol (30 ml), 1 mol/l of sodium hydroxide (30 ml) was added thereto, and the mixture was heated under reflux for 1.5 hours. After being allowed to cool, the mixture was neutralized with hydrobromic acid, then separated by filtration and washed with water. The washed product was subjected to through circulation drying to give the title compound (4.28 g, 97%) as a white powder.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([CH3:24])[CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:24])[CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1C
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Cc1cc(-c2nn(C3CCCC3)c3c(F)cccc23)ccc1O
Yield: 22.4 %

Procedure:
Prepared according to Method D step C from 1-cyclopentyl-7-fluoro-3-(4-methoxy-3-methylphenyl)-1H-indazole (0.70 g, 2.16 mmol), boron tribromide (0.82 mL, 8.6 mmol) and 1.0 mL of cyclohexene to give the product (0.15 g) as a white solid, mp 107° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5](CN=C=O)[CH:4]=[C:3]([CH2:11][N:12]=[C:13]=[O:14])C=1.C1(CN=C=O)C(C[N:22]=[C:23]=[O:24])=CC=CC=1>>[CH2:1]([N:22]=[C:23]=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:11][N:12]=[C:13]=[O:14]
Reactant: O=C=NCc1ccccc1CN=C=O
Reactant: O=C=NCc1cccc(CN=C=O)c1
Product: O=C=NCCCCCCN=C=O

Procedure:
The same isocyanuration reaction as in Example 1 was carried out except that 3,290 g of hexamethylene diisocyanate and 210 g of "Takenate 500" (xylylene diisocyanate produced by Takeda Chemical Industry Co., Ltd.) were used instead of 3,500 g of hexamethylene diisocyanate, and the amount of the isocyanuration catalyst used in Example 1 was changed to 4.7 g. There was obtained 4,219 g of the reaction mixture containing the deactivated catalyst.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[CH2:10][OH:11])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>ClCCl>[CH2:1]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH:12]([O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[CH3:13])[CH2:10][O:11][S:30]([CH3:29])(=[O:32])=[O:31])=[O:6])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)NCC(CO)C(C)O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)NCC(COS(C)(=O)=O)C(C)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 7.00 g of 2-(N-allyloxycarbonylaminomethyl)-3-t-butyldimethylsilyloxybutan-1-ol and 4.60 ml of triethylamine in 35 ml of dichloromethane was added dropwise 2.05 ml of methanesulfonyl chloride at -10° C. After stirring for 3 hours, water was added to the reaction mixture and then the solution was extracted with chloroform. The organic layer was washed in turn with 1N hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by a column chromatography on silica gel (hexane:ethyl acetate=3:1) gave 8.8 g of 2-(N-allyloxycarbonylaminomethyl)-3-t-butyldimethylsilyloxy-1-methanesulfonyloxybutane.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][NH2:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[CH2:23][C:24]1[N:28]2[N:29]=[C:30]([C:33](=O)[CH3:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1>>[F:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][C:14]=1[CH2:23][C:24]1[N:28]2[N:29]=[C:30](/[C:33](=[N:11]/[NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])/[CH3:34])[CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNC(=O)Nc1ccccc1
Product: C/C(=N\NC(=O)Nc1ccccc1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 36 %

Procedure:
The title compound was prepared from N-phenylhydrazine carboxamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 36% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.13 (s, 1H), 9.06 (s, 1H), 8.86 (dd, 1H), 8.30 (t, 2H), 8.06 (d, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.60 (d, 2H), 7.48 (q, 1H), 7.31 (t, 2H), 7.04 (t, 1H), 4.58 (s, 2H), 2.32 (s, 3H). LCMS (method C): [MH]+=454, tR=3.89 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9](Cl)=[O:10])=[O:5])[CH3:2].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.CCN(CC)CC>CCCCCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]([S:19][C:16]1[CH:17]=[CH:18][C:13]([CH3:12])=[CH:14][CH:15]=1)=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1C(=O)Cl
Reactant: Cc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C1CC1C(=O)Sc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of 2-chlorocarbonyl-cyclopropanecarboxylic acid ethyl ester (5.30 g, 30 mmol) and 4-methylbenzene thiol (3.73 g, 30 mmol) in 150 mL hexane at 0° C. was added a solution of Et3N in 25 mL hexane dropwise. The reaction was warmed to room temperature and stirred for 3 h. The solid precipitate was removed by filtration and washed with hexane. The filtrate was concentrated in vacuo to give 7.88 g (99%) of 2-p-tolylsulfanylcarbonyl-cyclopropanecarboxylic acid ethyl ester as an oil: 1H NMR (500 MHz, CDCl3) 7.30 (2H, d, J=7.93 Hz), 7.22 (2H, d, J=7.93 Hz), 4.17 (2H, q, J=7.02 Hz), 2.60 (1H, m), 2.37 (3H, s), 2.31 (1H, m), 1.54 (2H, m), 1.29 (3H, t, J=7.02 Hz). MS m/e 262.92 (M−H)−. Anal. calcd. for C14H16O3S: C, 63.61; H, 6.10. Found: C, 63.68; H, 6.17.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=3)[CH:13]=2)[N:8]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[C:7]=1[CH2:36][C:37]([OH:39])=[O:38])=[O:5])C.[OH-].[Na+]>CCO>[C:37]([CH2:36][C:7]1[N:8]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:31]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[CH:11][CH:10]=2)([OH:39])=[O:38]
Reactant: CCOC(=O)c1c(CC(=O)O)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cn3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-n2c(CC(=O)O)c(C(=O)O)c3cc(Oc4ccc(C(F)(F)F)cn4)ccc32)cc1

Procedure:
The title compound was prepared by heating 2-carboxymethyl-1-(4-isopropoxyphenyl)-5-(5-trifluoromethyl-2-pyridinyloxy)indole-3-carboxylic acid ethyl ester (140 mg, 0.26 mmol, see step (b) Example 25), NaOH (aq. 2 M, 0.6 mL) and EtOH (1 mL) at 90° C. for 7 h. Yield 124 mg (92%), nip 202° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH2:16])[NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([I:15])[CH:14]=1)[NH:11][CH:10]=[CH:9]2)#[N:2]>COCCOCCOC.CO>[I:15][C:13]1[C:12]2[NH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:6]([CH:14]=1)=[N:5][C:4]([NH2:16])=[N:3][C:1]=2[NH2:2]
Reactant: N#CN=C(N)Nc1cc(I)c2[nH]ccc2c1
Solvent: COCCOCCOC
Solvent: CO
Product: Nc1nc(N)c2c(cc(I)c3[nH]ccc32)n1
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of N″-cyano-N-(7-iodo-1H-indol-5-yl)guanidine V (6.08 g, 18.7 mmol) in 2-methoxyethyl ether (50 mL) was heated to 175° C. for 32.5 h. The reaction mixture was cooled to 25° C., the resulting solids removed by filtration and washed with methanol. The filtrate was concentrated in vacuo to give a brown oil. The residue was dissolved in methanol and then absorbed onto Merck Silica gel 60, 230–400 mesh (25 g). Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10/1 methylene chloride/methanol/ammonium hydroxide) afforded 6-iodo-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine VI (3.61 g, 59%) as a brown solid: 1H NMR (DMSO-d6, 300 MHz) δ 11.36 (broad s, 1H), 7.45 (broad s, 1H), 7.43 (t, J=2.93 Hz, 1H), 7.20 (s, 1H), 6.74 (broad s, 2H), 5.78 (broad s, 2H).