Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([C:14](=[O:34])[N:15]([CH:31]2[CH2:33][CH2:32]2)[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[CH2:11][C@H:10]([NH2:35])[CH2:9]1)=O)(C)(C)C.Cl[C:37]1[CH:42]=[C:41]([Cl:43])[N:40]=[CH:39][N:38]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.N1C(C)=CC=CC=1C>CC#N>[CH:31]1([N:15]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=2)[C:14]([C@@H:12]2[CH2:11][C@H:10]([NH:35][C:37]3[CH:42]=[C:41]([Cl:43])[N:40]=[CH:39][N:38]=3)[CH2:9][NH:8][CH2:13]2)=[O:34])[CH2:32][CH2:33]1
Reactant: Clc1cc(Cl)ncn1
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](Nc3cc(Cl)ncn3)C2)C2CC2)c2ccccc21

Procedure:
The title compound is prepared analogously as described in Example 154 using (3S*,5R*)-3-Amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester and 4,6-dichloropyrimidine followed by deprotection of Boc using TMSOTf and 2,6-lutidine. MS: 497 (Cl35) [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.77 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]([NH2:10])[C@H:2]1[OH:11].CCN(CC)CC.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[O:11]1[C@H:2]2[CH2:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C@H:3]2[NH:10][C:20]1=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N[C@@H]2c3ccccc3C[C@@H]2O1
Temperature: -60 °C

Procedure:
(1R,2S)-cis-1-amino-2-indanol (0.980 g, 6.569 mmol) was placed in a round-bottomed flask and a dry Ar atmosphere was established. Dry CH2Cl2 (50 mL) and Et3N (1.9 mL, 13.63 mmol) were added, and the resulting solution was cooled to −60° C. On addition of triphosgene (0.64 g, 2.157 mmol), the cooling bath was removed, and the reaction was allowed to warm to 20° C. over one hour. The reaction was then poured into CH2Cl2 (100 mL) and H2O (50 mL) and the aqueous phase was extracted with CH2Cl2 (3×100 mL). After drying with MgSO4, the organic layer was evaporated under reduced pressure to give (3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]-oxazol-2-one, (R)-24 (1.15 g, quantitative) as white crystals, which was of sufficient purity for the next step in the reaction sequence. An analytical sample was recrystallized from CH2Cl2/hexanes. mp 205.5-206.5° C.; [Ghosh et al. (1992) J. Chem. Soc. Chem. Commun. 1673-1674 for enantiomer mp 205° C.]; [α]25D=+107.7 (c 1.25, CHCl3); [Id. for enantiomer [α]25D=−79.4 (c 1.4, CHCl3)]. IR (KBr) 3255, 1752, 1707 cm−1; 1H NMR (acetone-d6) δ 7.24-7.43 (4H, m), 5.39 (1H, t, J=7.5 Hz), 5.21 (1H, d, J=7.0 Hz), 3.42 (1H, dd, J=17.7, 6.2 Hz), 3.20 (1H, d, J=17.9 Hz), 2.90 (1H, br s); 13C NMR (acetone-d6) δ 159.1, 142.5, 141.0, 129.7, 128.3, 126.2, 125.8, 80.8, 61.7, 39.3; HRMS (FAB+) m/z: calcd for C10H9NO2+H, 176.0771; found, 176.0681.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:12](=O)[NH:13][N:14]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:24])=O>C1C=CC=CC=1>[Cl:24][C:12]1[N:13]=[N:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=1
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccccc2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(-c2nnc(Cl)cc2-c2ccccc2)cc1

Procedure:
6-(4-Methoxyphenyl)-5-phenyl-2H-pyridazin-3-one [WO 9925697] (2.76 g, 9.60 mmol) and phosphorus oxychloride (2.8 mP) were stirred at 90° C. for 5 hours in benzene. The reaction mixture was processed in a similar manner as in Example 22, whereby the title compound was obtained as a pale yellow-brown oil (1.83 g, 64.3%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2c[nH]c3ccccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Clc1cccc(C2CNc3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-(3-Chlorophenyl)indole (5.30 g, 23.3 mmol) was dissolved in 50 mL of 1 M BH3 in THF. The mixture was cooled to about 0° C. To the solution was added slowly TFA (50 mL). After addition, the solution was stirred for about 10 minutes. To the solution was added slowly 1M BH3 in THF (40 mL). The mixture was stirred for about 5 minutes and then concentrated in vacuo. The residue was purified by column chromatography on silica, eluting with EtOAc/hexane 1:6. The title compound was obtained as an oil (Yield; 3.93 g, 74%). Rf=0.20 (Silica, EtOAc/hexane 1:4) MS (ES):229.1; Calc. MW=229.7.)
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[C:37]([O:41][C:42]([NH:44][C@@H:45]([CH:49]([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:46](=[O:47])[C@@H:45]([NH:44][C:42]([O:41][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:43])[CH:49]([CH3:51])[CH3:50])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
The solution of 300 mg (0.59 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one in 3 ml of pyridine was admixed with 14 mg of 4-dimethylaminopyridine, 383 mg of (S)-2-tert-butoxycarbonylamino-3-methylbutanoic acid and 130 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the mixture was stirred at 23° C. for 16 hours. The mixture was poured into water and extracted repeatedly with dichloromethane, and the combined organic extracts were washed with water and saturated sodium chloride solution and dried over sodium sulphate. The residue obtained after filtration and solvent removal was purified by chromatography. 314 mg (75%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[NH2:41]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:41][C:35]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=3[F:33])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][C:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=5[O:25][CH2:24]4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Reactant: Cc1ccc(F)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 51.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.250 g, 0.546 mmol) obtained in Example 145, step 2 and 2-fluoro-5-methylphenylamine (0.150 mL, 1.37 mmol), the title compound (0.155 g, 52%) was obtained.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.[CH3:19]I>>[CH3:19][N:6]1[S:2](=[O:1])(=[O:18])[N:3]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc(N2CCNS2(=O)=O)cc1
Reactant: CI
Product: CCOC(=O)c1ccc(N2CCN(C)S2(=O)=O)cc1

Procedure:
Using ethyl 4-(1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)benzoate (195 mg) described in Preparation Example 46 and methyl iodide (99 μL) and by the reaction and treatment in the same manner as in Example 36, crude ethyl 4-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)benzoate (107 mg) was obtained. Using the obtained crude ethyl 4-(5-methyl-1,1-dioxo-1λ6-[1,2,5]thiadiazolidin-2-yl)benzoate (107 mg) and 1-(3,5-dimethylpyridin-2-yl)piperazine (75.7 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (120 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:8]2[C:9]3[C:4](=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=3)[CH2:5][CH:6]([C:12]([OH:14])=[O:13])[NH:7]2)=[O:24])=[CH:18][CH:17]=1
Reactant: O=C(O)C1Cc2cc(O)ccc2CN1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C(O)C1Cc2cc(O)ccc2C(C(=O)Nc2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a suspension of (D,L) 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (500 mg, 2.59 mmol) in DMF (12 mL), 4-chlorophenyl isocyanate (400 mg, 2.60 mmol) was added. The reaction mixture was stirred at room temperature overnight, and the suspension became clear solution. It was then concentrated in vacuo. The residue was dissolved in CH2Cl2, and the product was extracted with 5N NaOH. The alkaline solution was then separated, acidified with 4N HCl to pH 2-3. The cloudy mixture was extracted with EtOAc. The EtOAc solution was dried over Na2SO4, concentrated in vacuo to give the titled compound as a solid (841 mg), which was pure enough for the next reaction.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([CH2:9][CH3:10])[C:7](=[O:11])[C:6]([CH3:12])=[C:5]([OH:13])[N:4]=1)[CH3:2].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([C:3]1[N:8]([CH2:9][CH3:10])[C:7](=[O:11])[C:6]([CH3:12])=[C:5]([O:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[N:4]=1)[CH3:2]
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Reactant: CCc1nc(O)c(C)c(=O)n1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc(OCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(C)c(=O)n1CC
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
In 15 ml of N,N-dimethylformamide were dissolved 0.91 g of 2,3-diethyl-6-hydroxy-5-methyl-4(3H)-pyrimidinone and 1.66 g of 4-(4'-trifluoromethylphenoxy)benzyl bromide, and then 0.69 g of potassium carbonate was added thereto. The mixture was stirred for 18 hours at room temperature. The resulting solution was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The oil thus obtained was purified by means of column chromatography (on silica gel, eluting with benzene) to give 1.35 g of the intended product.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[N:21][CH:22]=2)=[CH:13][C:12]([C:36]2[CH:41]=[C:40]([Cl:42])[C:39]([OH:43])=[C:38]([Cl:44])[CH:37]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C:17]2[CH:22]=[N:21][C:20]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:19][CH:18]=2)=[CH:13][C:12]([C:36]2[CH:37]=[C:38]([Cl:44])[C:39]([OH:43])=[C:40]([Cl:42])[CH:41]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCNCC2)nc1)C1CC1
Yield: 41.2 %

Procedure:
Following general procedure A-2, tert-butyl 4-{5-[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino]pyridin-2-yl}piperazine-1-carboxylate (0.118 mmol) was reacted with TFA (2 mL) to afford the desired product (26 mg, 41% over two steps) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 11.92 (s, 1H), 9.35 (s, 1H), 8.07-7.94 (m, 2H), 7.75-7.68 (m, 2H), 7.08-7.02 (m, 2H), 6.72-6.65 (m, 1H), 3.71-3.64 (m, 4H), 3.17-3.10 (m, 4H), 2.84-2.77 (m, 1H), 1.34-1.10 (m, 4H); ESI MS m/z 534 [C28H25Cl2N5O2+H]+; HPLC 97.3% (AUC), tR=8.65 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]1[CH:21]=[C:22](O)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[C:24]([F:26])[CH:25]=1)[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: Oc1cc(F)cc(F)c1
Product: CO[C@@H](Cc1ccc(OCCCOc2cc(F)cc(F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 3,5-difluorophenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: ClCC(O)=[O:4].S[C:7]1[NH:12][C:11](=[O:13])[CH:10]=[C:9]([CH2:14][CH3:15])[N:8]=1.Cl>O>[OH:4][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([CH2:14][CH3:15])[N:8]=1
Reactant: CCc1cc(=O)[nH]c(S)n1
Reactant: O=C(O)CCl
Agent: Cl
Solvent: O
Product: CCc1cc(O)nc(O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture solution of chloroacetic acid(33.3 g, 0.352 mol), water(400 ml) and 2-mercapto-6-ethylpyrimidine-4-one(29 g, 0.186 mol) prepared in the above Step 1 was heated to reflux for 14 hours and cooled to a room temperature. To the reaction mixture was added conc. HCl(95 ml) and the mixture was heated to reflux for 1 day. After the reaction mixture was cooled to a room temperature and concentrated under a reduced pressure, the residue was diluted with water. After stirring for 2 hours, the resulting solid was filtered and dried to give 11.16 g of the titled compound. (Yield: 43%)
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30](=O)[C:31]([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:29]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)C(=O)CBr
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: CC(C)(C)c1csc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 48 mg (0.269 mmol) of 1-bromo-3,3-dimethylbutan-2-one were reacted according to the General Method 3. Yield: 19 mg (17% of theory)
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH3:14][CH:15]([NH2:19])[CH:16]([CH3:18])[CH3:17]>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:19][CH:15]([CH3:14])[CH:16]([CH3:18])[CH3:17])[NH:7][C:6]=2[CH:8]=1
Reactant: CC(C)C(C)N
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Product: CC(C)C(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1
Yield: 72 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.5 g, 1.94 mmol) in 1,2-dimethylpropylamine (5 ml) was stirred for 48 h at 100° C in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was stirred with water (20 ml) followed by adjustment to pH 2 with 4M hydrochloric acid. The initially formed gummy product crystallised by stirring the mixture for about 2 h at 0° C. The precipitate was isolated by filtration, washed with water, and recrystallised from ethyl acetate/methanol followed by drying in vacuo at 60° C. over night to give 0.43 g (72%) of the pure title compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH:19]([F:21])[F:20])[NH:14][CH:13]=[CH:12]2)C1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[C].[Pd]>[F:21][CH:19]([F:20])[O:18][C:17]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][C:9]=1[OH:8]
Reactant: FC(F)Oc1cc2[nH]ccc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1cc2cc[nH]c2cc1OC(F)F
Reaction time: 1.25 h

Procedure:
5-(Benzyloxy)-6-(difluoromethoxy)-1H-indole described in Production Example 19-4 (245 mg, 0.847 mmol) was dissolved in ethanol (8.0 mL), then 10% palladium-carbon (water content, 50%) (90 mg) was added at room temperature, and the mixture was stirred under hydrogen atmosphere for 75 minutes. The reaction mixture was diluted with ethyl acetate and the catalyst was filtered off with celite. The filtrate was concentrated under vacuum and then filtered with silica gel (ethyl acetate). The target fraction was concentrated under vacuum to quantitatively obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([O:23]CC)=O)[N:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:30][CH2:29]1.C[Al](C)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][N:19]=[C:18]([C:21]([N:38]3[CH2:37][CH2:36][N:35]([CH2:34][CH:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH2:40][CH2:39]3)=[O:23])[N:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)c1noc(CN(C)S(=O)(=O)c2c(C)cc(OC)cc2C)n1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)no2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AT using ethyl 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,2,4-oxadiazole-3-carboxylate (35 mg, 0.09 mmol), 1-[(1-methylpiperidin-4-yl)methyl]piperazine (34 mg, 0.17 mmol) and trimethylaluminium (2 M in toluene, 0.08 mL) in DCE (3 mL). A portion of the crude product was purified using prep method D.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[OH:22]O>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:22])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: N#Cc1cc(Sc2ccccc2)[nH]c1-c1ccc(Cl)cc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(S(=O)c2ccccc2)[nH]c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.9 %

Procedure:
A mixture of 2-(p-chlorophenyl)-5-(phenylthio)pyrrole-3-carbonitrile (916 mg, 2.95 mmol) and 30% hydrogen peroxide solution (105.3 mg, 3.09 mmol) in acetic acid is stirred at room temperature for 3 days, diluted with water and filtered to obtain a solid. The solid is recrystallized from methanol to give the title product as a grey solid (510 mg, mp 169°-170° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][CH:29]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:30][CH2:31]O)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)=[N:6][CH:7]=1.[N+:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Se:46]C#N)([O-:39])=[O:38].C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:36][C:33]([CH3:34])([CH3:35])[CH:29]([NH:28][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:9]=2)[N:4]=1)[CH2:30][CH2:31][Se:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[N+:37]([O-:39])=[O:38]
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CCO)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(CC[Se]c4ccccc4[N+](=O)[O-])C(C)(C)C)n3)c3cc(F)cnc32)cc1
Reaction time: 8 h

Procedure:
To a solution of racemic 3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]-4,4-dimethyl-pentan-1-ol, 82a, (1.093 g, 2.120 mmol) and (2-nitrophenyl) selenocyanate (0.722 g, 3.180 mmol) in THF (8 mL) was added tributylphosphane (0.792 mL, 3.180 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The crude residue was purified by silica gel (0 to 100% EtOAc/Hexanes gradient) to afford 1.20 g of the desired product.
Reaction SMILES: Cl.Cl.C([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([NH:21][C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]4[O:29][CH2:30][O:31][C:23]=34)=[N:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:32][CH3:33])C1C=CC=CC=1>FC(F)(F)C(O)=O>[Cl:28][C:27]1[C:22]([NH:21][C:15]2[C:14]3[C:19](=[CH:20][C:11]([OH:10])=[C:12]([O:32][CH3:33])[CH:13]=3)[N:18]=[CH:17][N:16]=2)=[C:23]2[O:31][CH2:30][O:29][C:24]2=[CH:25][CH:26]=1
Reactant: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(Cl)ccc4c3OCO4)ncnc2cc1O
Yield: 111.5 %

Procedure:
A mixture of 7-benzyloxy-4-(6-chloro-2,3-methylenedioxyanilino)-6-methoxyquinazoline dihydrochloride (3.3 g) and trifluoroacetic acid (60 ml) was heated to reflux for 4 hours. The mixture was evaporated. The residue was diluted with water and methanol and the mixture was basified to pH 7.5 by the addition of a saturated aqueous sodium carbonate solution. The methanol was evaporated and the resultant solid was isolated and washed with water. There was thus obtained the title compound as a solid (2.5 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 3.95 (s, 3H), 6.1 (s, 2H), 6.95 (d, 1H), 7.1 (m, 2H), 8.1 (s, 1H), 8.4 (s, 1H), 9.85 (br s, 1H), 10.7 (br s, 1H); Mass Spectrum: M+H+ 346 and 348.
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:13][CH:14]([CH2:16]O)O.[OH-].[NH4+].C(O)(=O)C>O>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:16][CH:14]=[CH:13]2
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2cccnc12
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 2-methyl-3-nitroaniline (10 g), glycerin (20.57 g) and As2O5.xH2O (Baker, 88% As2 O5, 8.5 g) is heated slowly to 150° C. in an open round-bottom flask, then stirred for 6 hrs at 150° C. The resulting mixture is cooled to room temperature and diluted with water (200 mL), then basified with ammonium hydroxide (28-30%, 100 mL). After about 10 minutes, the solution is acidified to pH=5 with glacial acetic acid and extracted with CH2Cl2 (3×200 mL). The combined extracts are washed with H2O (200 mL), sat. NaHCO3 (200 mL), then dried over MgSO4 and rotary evaporated. The crude quinoline is filtered through a short pad of silica gel, using CH2Cl2 as solvent. The filtrate is rotary evaporated and the residue recrystallized from hexane/CH2Cl2 to afford 8-methyl-7-nitroquinoline as a tan solid.