Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][CH:20]=C)[CH3:16])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C[N+]1([O-])CC[O:33]CC1.OS([O-])=O.[Na+].I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.C(O)(C)(C)C.O.[Cl-].[Na+].O.O=[Os](=O)(=O)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([N:15]([CH2:17][C@H:18]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][CH:20]=[O:33])[CH3:16])=[O:14])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(C#N)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
3-Cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (460 mg, 1.22 mmol) was dissolved in a mixture of acetone (8 mL), t-butyl alcohol (4 mL) and water (2 mL) under nitrogen. OsO4 (2.5% in t-butyl alcohol, 0.165 mL, 0.01 mmol) was added together with 4-methylmorpholine-4-oxide (630 mg, 5.4 mmol). The solution was stirred at room temperature for 5 h and then an aqueous solution of NaHSO3 (39%, 12 mL) was added. The mixture was stirred for 15 min, diluted with water (50 mL) and then extracted three times with CH2Cl2. The organic solution was dried over Na2SO4 and then the solvent was evaporated. The residue (570 mg) is was dissolved in a mixture of THF (7 mL) and water (3 mL) and to the resultant solution was added sodium periodate (287 mg, 1.34 mmol). The mixture was stirred at room temperature overnight, diluted with water (50 mL) and brine (30 mL) and then extracted twice with CH2Cl2. The organic solution was dried over Na2SO4 and then the solvent was evaporated. There was obtained 415 mg (89%) of 3-cyano-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil. 1H NMR (400 MHz, CDCl3): 1.4-4.2 (cm, 16H), 6.6-7.4 (cm, 6H), 9.7 (s, 1H); LCMS: m/z 379 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:31][O:32]C)[CH2:9][CH2:8][N:7]([C:10](=[O:30])[CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH2:6]1)=O.[OH-].[Na+].Cl.[CH:37]1([C:40]2[CH:45]=[C:44]([C:46]3[C:54]4[C:49](=[CH:50][CH:51]=[C:52]([NH2:55])[CH:53]=4)[N:48]([C:56]([C:69]4[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=4)([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[N:47]=3)[CH:43]=[CH:42][N:41]=2)[CH2:39][CH2:38]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O.ClCCl.CO.ClCCl>[CH:37]1([C:40]2[CH:45]=[C:44]([C:46]3[C:54]4[C:49](=[CH:50][CH:51]=[C:52]([NH:55][C:31]([C:5]5([CH2:3][O:2][CH3:1])[CH2:9][CH2:8][N:7]([C:10](=[O:30])[CH2:11][N:12]6[CH2:17][CH:16]=[C:15]([C:18]7[CH:19]=[CH:20][C:21]([C:24]8[N:29]=[CH:28][CH:27]=[CH:26][N:25]=8)=[CH:22][CH:23]=7)[CH2:14][CH2:13]6)[CH2:6]5)=[O:32])[CH:53]=4)[N:48]([C:56]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)[C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)[N:47]=3)[CH:43]=[CH:42][N:41]=2)[CH2:38][CH2:39]1
Reactant: Nc1ccc2c(c1)c(-c1ccnc(C3CC3)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCC1(C(=O)OC)CCN(C(=O)CN2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1(C(=O)Nc2ccc3c(c2)c(-c2ccnc(C4CC4)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(C(=O)CN2CC=C(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 18 h
Yield: 56.4 %

Procedure:
3-Methoxymethyl-1-{2-[4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-acetyl}-pyrrolidine-3-carboxylic acid methyl ester (500 mg, 1.11 mmol) was added to a solution of 10 ml of 50% methanol/dichloromethane. 5 mL of 1N NaOH was added and the reaction mixture stirred for 18 hrs. 5.5 ml of 1N HCl was added and the reaction mixture evaporated to dryness. To the crude reaction mixture was added 3-(2-Cyclopropyl-pyridin-4-yl)-1-trityl-1H-indazol-5-ylamine (601 mg, 1.22 mmol), HATU (464 mg, 6.66 mmol), triethylamine (0.93 ml, 6.66 mmol) and 10 ml of 50% N,N-dimethylformamide/dichloromethane. The reaction mixture was stirred for 18 hrs. followed by washing with brine and extracted with ethylacetate 3×. After evaporation of the organic layers, the crude reaction mixture was chromatographed on silica gel using 1-3% 2N NH3/methanol/dichlormethane as the eluent to obtain 570 mg of title product.
Reaction SMILES: I[CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:10]=[CH:11][C:12]3[S:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=3[CH:19]=2)[CH2:4]1.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C=O)C.O.CC(OC)(C)C>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][C@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:10]=[CH:11][C:12]4[S:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=4[CH:19]=3)[CH2:4]2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C1CSc2ccc(N3C[C@@H](CI)OC3=O)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)CC1

Procedure:
A solution of 6-((S)-5-iodomethyl-2-oxooxazolidin-3-yl)-4H-benzo[1,4]thiazin-3-one (prepared according to WO 2008/126034; 1.0 g) and Boc-piperazine (1.43 g) in DMF (10 ml) was stirred overnight at rt and 2 h at 60° C. The reaction mixture was allowed to reach rt, diluted with water and extracted with EA (2×). The combined org. layers were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure, affording after stirring the residue in TBME a colourless solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:36])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:33][CH3:34])[C:25]([NH:27][C:28]([CH3:32])([CH3:31])[CH2:29]O)=[O:26])[C:5]1=[O:35])[CH:2]=[CH2:3].C(N(S(F)(F)F)CC)C.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:36])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([C:25]2[O:26][CH2:32][C:28]([CH3:31])([CH3:29])[N:27]=2)[CH2:33][CH3:34])[C:5]1=[O:35])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)C(=O)NC(C)(C)CO)C1=O
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C2=NC(C)(C)CO2)C1=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a cold (−78° C.) solution of 2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)butanamide (89 mg, 0.167 mmol; Example 179, Step A: epimeric mixture) in DCM (1674 μL) was added 3 eq. of diethylaminosulfur trifluoride (26.5 μL, 0.201 mmol) dropwise. The reaction mixture was stirred at −78° C. for 20 min. Anhydrous K2CO3 (1.5 equiv) was then added in one portion and the mixture was allowed to warm to ambient temperature. The reaction was poured into saturated aqueous NaHCO3, and the biphasic mixture was extracted with EtOAc×2. The combined organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 0 to 20% ethyl acetate/hexane) provided the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[CH:10][CH:9]=1
Reactant: O=C(CCCCCl)c1ccc(Br)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(4-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:32]([Sn:36](Cl)([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn:36]([CH2:37][CH2:38][CH2:39][CH3:40])([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:32][CH2:33][CH2:34][CH3:35])[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)c(Cl)c3)cc(C(F)(F)F)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a stirred solution of 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example E.74) (1.46 g, 3.0 mmol) in THF (21 mL) was added at 0° C. isopropyl-magnesium chloride lithium chloride (1M in THF, 3.6 mL, 3.6 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (1.27 g, 3.9 mmol) was added, the reaction mixture was stirred at room temperature for 16 h, poured into saturated ammonium chloride solution (70 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (70 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on a lox (ethylacetate/heptane) to yield the title compound (0.47 g, 24%) as a light yellow oil. MS (ISP) 649.2 [(M+H)+].
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]1([CH2:21][CH2:22][NH:23][CH:24]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>O>[CH:24]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:21][CH2:22][N:23]=1
Reactant: O=CNCCc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C1=NCCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
Polyphosphoric acid (25 g) and phosphorus pentoxide (5.4 g, 38.0 mmol) were heated to 180° C. over the course of one hour in an oil bath under an argon atmosphere. N-Phenylethylformamide (146) (4.3 g, 28.8 mmol) was then added at 160° C., and the mixture was stirred for 1.5 hours at constant temperature. The mixture was then allowed to cool to room temperature, and water (40 ml) was added. The mixture was subsequently adjusted to pH 10 by careful addition of saturated aqueous NaOH solution. The mixture was then extracted with ether (500 ml), and the organic phase was separated off and dried using NaOH. Evaporation gave a brown oil (2.81 g, 21.4 mmol, 74%).
Reaction SMILES: [CH:1]1([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH:21]2CCCC[CH2:22]2)=[O:19])=[O:9])CCCC[CH2:2]1>C(O)C>[CH2:21]([O:20][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:8]([O:7][CH2:1][CH3:2])=[O:9])=[O:19])[CH3:22]
Reactant: O=C(NCCCCCCNC(=O)OC1CCCCC1)OC1CCCCC1
Solvent: CCO
Product: CCOC(=O)NCCCCCCNC(=O)OCC
Temperature: 230 °C
Yield: 92.2 %

Procedure:
368 g of 1,6-bis-(cyclohexoxycarbonylamino)-hexane (1 mol) were dissolved in 1.5 l ethanol and heated for two hours at 230° C. in a 3 l autoclave. After cooling, the reaction mixture was separated from the excess ethanol and resultant cyclohexanol in a water jet vacuum. The reaction product was examined by high pressure liquid chromatography (HPLC). A yield of 240 g of 1,6-bis-(ethoxycarbonylamino)-hexane was produced corresponding to a yield of 92% of the theoretical yield.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[OH-].[K+]>O.C(O)C>[OH:22][C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][N:26]([CH2:3][C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH2:25][CH2:24]1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC1(c2ccccc2)CCN(Cc2cccc(OCc3ccc4ccccc4n3)c2)CC1
Yield: 47.1 %

Procedure:
A mixture of 3.2 g (0.01 mol) 2-(3-chloromethyl-phenoxymethyl)quinoline hydrochloride, 1.7 g (0.01 mol) 4-hydroxy-4-phenylpiperidine and 1.2 g (0.02 mol) KOH in 5 ml of H2O and 50 ml ethanol was heated over steam bath for a period of 3 hours. Reaction mixture was concentrated to dryness and slurried into water, and extracted with methylene chloride. The methylene chloride extract dried over MgSO4 and concentrated to dryness under reduced pressure to obtain solid. Repeated recrystallization from isopropanol and acetronitrite gave desired product 2 g, m.p. 123°-225° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]2[C:5]([C:6](=O)[CH2:7][C:8]3([O:14]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.Cl.[O:19]([NH2:21])[CH3:20].N1C=CC=CC=1>CO>[CH3:20][O:19][N:21]=[C:6]1[C:5]2[C:15](=[CH:16][C:2]([OH:1])=[CH:3][CH:4]=2)[O:14][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:7]1
Reactant: CON
Reactant: O=C1CC2(CCCCC2)Oc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CC2(CCCCC2)Oc2cc(O)ccc21

Procedure:
The product from Example 16A (479 mg, 2.06 mmol), methoxylamine hydrochloride (275 mg, 3.29 mmol), and pyridine (0.36 mL, 4.45 mmol) were stirred in methanol (5 mL) at room temperature overnight. After this time, the solvent was evaporated in vacuo, and the residue was taken up in ethyl acetate and washed with 1N HCl and brine. The organic solution was dried over Na2SO4 and was evaporated in vacuo. Chromatography on silica gel (4:1 hexane-ethyl acetate, eluant) afforded the title compound as a colorless oil, 524 mg (97%). 1H NMR (300 MHz, DMSO-d6) δ 9.79 (br, 1H), 7.54 (d, J=8.8 Hz, 1H), 6.35 (m, 1H), 6.22 (m, 1H), 3.84 (s, 3H), 2.68 (s, 2H), 1.25-1.79 (m, 10H). MS (DCI+) m/z 262 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[CH:7][N:6]=1)=[O:4]>[Pd].C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(O)cn1

Procedure:
A mixture of 7.9 g of 5-benzyloxy-2-pyridinecarboxylic acid methyl ester, 100 ml of 75% aqueous ethanol and 0.2 g of palladium over carbon (5%) is hydrogenated at 47 psi at room temperature. After the theoretical uptake of hydrogen, the mixture is filtered and the filtrate evaporated to yield 5-hydroxy-2-pyridinecarboxylic acid methyl ester melting at 191.5°-192.5°.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.N1[C:19]2[C:14](=[C:15]([C:20](C3C=CC=CC=3)=[CH:21][C:22]#[N:23])[CH:16]=[CH:17][CH:18]=2)C=C1>>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=3)=[CH:21][C:22]#[N:23])[CH:10]=2)[CH:6]=[CH:7]1
Reactant: N#CC=C(c1ccccc1)c1cccc2[nH]ccc12
Reactant: Brc1ccc2cc[nH]c2c1
Product: N#CC=C(c1ccccc1)c1ccc2cc[nH]c2c1
Yield: 61 %

Procedure:
3-(1H-Indol-6-yl)-3-phenyl-acrylonitrile XII (1.46 g, 61% yield) was prepared from 6-bromo-indole using the procedure described for 3-(1H-indol-4-yl)-3-phenyl-acrylonitrile I.
Reaction SMILES: C(P(CCCC)CCCC)CCC.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Cl:21][SiH:22]([Cl:24])[Cl:23]>>[CH2:15]([Si:22]([Cl:24])([Cl:23])[Cl:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Cl[SiH](Cl)Cl
Reactant: CCCCCCCl
Agent: CCCCP(CCCC)CCCC
Product: CCCCCC[Si](Cl)(Cl)Cl
Temperature: 150 °C
Yield: 66.8 %

Procedure:
In a 25 ml oven dried stainless steel tube, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 0.90 g (7.5 mmol) of 1-chlorohexane, and 5.08 g (37.5 mmol) of trichlorosilane were added under a dry nitrogen atmosphere. After sealing the cylinder with a valve, the reactor was maintained at 150° C. for 12 hrs. The resulting mixture was distilled to yield 1.1 g of n-hexyltrichlorosilane (bp; 215-219° C., yield; 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:11]=1)[N:8]=[C:7]([CH3:16])[CH:6]=[CH:5]2.[Se](=O)=[O:18]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([CH3:14])[CH3:15])[CH:11]=1)[N:8]=[C:7]([CH:16]=[O:18])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(OC(C)C)c2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1cc(F)cc2ccc(C=O)nc12
Yield: 35 %

Procedure:
To 6-fluoro-8-isopropoxy-2-methylquinoline (1.1 g, 5.02 mmol) in dioxane/water (3.5 ml/0.3 mL) at ambient temperature was added selenium dioxide (0.668 g, 6.02 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-8-isopropoxyquinoline-2-carbaldehyde (410 mg, 35.0% yield) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:43])[CH2:4][C:5]1[C:6]([CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])[CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1cccnc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-(4-((4-((3-(2-methoxy-2-oxoethyl)pyridin-2-yl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I147) (0.061 g, 0.10 mmol) in DMF (9 mL) and triethylamine (1 mL) was added a slurry of Pd/C (0.070 g) in DMF (3 mL). The resulting mixture was stirred under an atmosphere of hydrogen at room temperature for 16 hours. The crude reaction mixture was diluted with ethyl acetate then filtered through a pad of Celite. The Celite was washed with ethyl acetate and the filtrates combined. The solvent was removed in vacuo to give a brown oil which was taken up in DMF (9 mL) and triethylamine (1 mL). A slurry of Pd/C (0.070 g) in DMF (3 mL) was added and the resulting mixture was stirred under an atmosphere of hydrogen at room temperature for a further 19 hours. The crude reaction mixture was diluted with ethyl acetate then filtered through a pad of Celite. The Celite was washed with ethyl acetate and the filtrates combined. The solvent was removed in vacuo to give a brown oil which was chromatographed (Biotage Isolera: 25 g silica cartridge, 0-50% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I148) (0.030 g, 49%) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.46 (dd, J=4.8, 1.7 Hz, 1H), 7.61-7.46 (m, 4H, NH), 7.19 (d, J=8.6 Hz, 2H), 7.12 (dd, J=7.7, 4.8 Hz, 1H), 4.35-3.99 (m), 3.72 (s, 2H), 3.70 (s, 3H), 3.37 (J=7.4 Hz, 2H), 3.28 (t, J=6.9 Hz, 2H), 2.80-2.57 (m, 3H), 2.07-1.95 (m), 1.91-1.69 (m, 2H), 1.69-1.50 (m, 3H), 1.46 (s, 9H). LCMS Method C: rt=6.00 min, m/z 600.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=O)[N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>C1COCC1>[CH3:1][C:2]1([CH3:25])[CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[C@@H:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C)(C)C[C@@H]1C(=O)OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)C[C@H](C(=O)OCc2ccccc2)N(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of (R)-2-benzyl 1-tert-butyl 4,4-dimethyl-5-oxopyrrolidine-1,2-dicarboxylate (D39) (210 mg, 0.6 mmol) in THF (10 ml) cooled at −78° C., LiEt3BH 1M sol in THF (0.6 ml) was added and the mixture stirred 2 hrs at −78° C. The reaction was warmed to 0° C. and quenched with slow addition of NaHCO3 sat sol (4 ml) and 1 drop of H2O2. Stirring was continued for 20 min then THF was removed under reduced pressure and the remaining residue was taken up in water (5 ml) and extracted with DCM (3×10 ml). The organic phases were collected, dried over Na2SO4 and evaporated in vacuo. The obtained residue was dissolved in DCM (10 ml) and cooled at −78° C. under N2. Et3SiH (0.09 ml, 0.6 mmol) was added followed by addition of BF3.OEt2 (0.1 ml, 0.63 mmol) and the reaction stirred 30 min, prior further addition of Et3SiH (0.09 ml, 0.6 mmol) and BF3.OEt2 (0.1 ml, 0.63 mmol). The final reaction mixture was stirred at −78° C. for 3 hrs then quenched by the slow addition of saturated NaHCO3 and water. The reaction mixture was extracted with DCM (3×10 ml), the organic layers washed with NaCl sat sol, dried over Na2SO4 and evaporated to afford the title compound (D40) (168 mg).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:10][CH:11]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 31.4 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(4-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.26 g) in dichloromethane (6 mL) was added TFA 1.(6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as an off-white solid (0.073 g, 10%). MS (ISN) 478.0 [(M−H)−]; mp 324° C.