Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+]>C(OC(C)(C)C)(=O)C>[C:8]([O:1][CH:2]([C:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[OH:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([CH3:17])([CH3:9])[CH3:2]
Reactant: CCOC(=O)C(O)c1c(C)cc2ccccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1O
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A solution of ethyl 2-hydroxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (622 mg, 2.39 mmol) in tert-butyl acetate (12 mL) was treated with 70% HClO4 (20 μL) at 23° C.). After 3 h, the reaction was added slowly over 5 min to saturated NaHCO3 (25 mL). The resulting system was extracted with DCM (3×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. Hexane (10 mL) was added, and the mixture was concentrated again. The residue was dissolved in benzene. The solution was wet-loaded onto a 24 g “gold” ISCO silica gel column and purified by flash chromatography (hexane→ethyl acetate) giving the desired product (286 mg, 38% yield). 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.2, 8.0 Hz, 1H), 7/39 (dd, J=8.8, 8.0 Hz, 1H), 7.17 (s, 1H), 5.52 (s, 1H), 4.25-4.06 (m, 2H), 2.59 (s, 3H), 1.33 (s, 9H), 1.20 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15](Br)=[C:14]2[C:10]=1[C:11]([CH2:21][C:22]([NH:24][CH3:25])=[O:23])=[CH:12][N:13]2[CH3:20])C1C=CC=CC=1.N1C=CC=CC=1.Cl>CO.[Pd]>[F:18][C:17]1[C:9]([OH:8])=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:20])[CH:12]=[C:11]2[CH2:21][C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)Cc1cn(C)c2c(Br)cc(F)c(OCc3ccccc3)c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CNC(=O)Cc1cn(C)c2ccc(F)c(O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
A mixture of 33-5 (1.4 g, 4.5 mmol), pyridine (2 mL) and Pd/C (140 mg, 10%) in methanol (20 mL) was stirred at room temperature overnight under hydrogen atmosphere. The mixture was adjusted with hydrochloric acid to pH=5-6. The solid was filtered off and the filtrate was concentrated. The resulting residue was partitioned between water (20 mL) and ethylacetate (20 mL). The organic layer was separated, washed with brine (3×30 mL), dried over MgSO4, filtered and evaporated to obtain 33-6 (700 mg, 85%) as a brown solid. LRMS: calc 236.1 and found: 237.1 [M+1].
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.Br[C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:32](=[O:41])/[CH:33]=[CH:34]/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:16][C:17]([N:19]2[CH2:23][CH2:22][C@H:21]([NH:24]C(=O)OC(C)(C)C)[CH2:20]2)=[O:18])=[CH:11][CH:10]=1>ClCCl>[NH2:24][C@H:21]1[CH2:22][CH2:23][N:19]([C:17](=[O:18])[CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:5][C:3]3[CH:2]=[CH:11][CH:10]=[CH:9][CH:14]=3)=[CH:10][CH:11]=2)[C:32](=[O:41])/[CH:33]=[CH:34]/[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:20]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Br)cc2)C1
Solvent: ClCCl
Product: N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
Trifluoroacetic acid (30 mL) was added to a solution of [(S)-1-(2-{(4-bromophenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamic acid, tert-butyl ester 3 (4.0 g, 7.57 mmol) in dichloromethane (90 mL). The reaction mixture was stirred at room temperature for 16 h, and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1M NaOH (×2), brine, dried (Na2SO4) and evaporated to give the title compound as a foam (2.78 g, 86%). 1HNMR (300 MHz) (d6-DMSO) δ 1.5-2.1 (2H, 4×m), 3.08 (1H, m), 3.1-3.6 (4H, m), 4.47, 4.50 (2H, 2×br s), 6.43 (1H, br d), 7.3-7.5 (7H, m), 7.53 (1H, d, J=16 Hz) and 7.65 (2H, d).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:1][C:2]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:15]([O:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)[N:14]=1)=[O:12])([C:4]1[N:8]=[C:7]([CH3:9])[O:6][N:5]=1)[CH3:3]
Reactant: OC1CNC1
Reactant: Cc1nc(C(C)(C)NC(=O)c2ccc(Br)c(OCC3CC3)n2)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CC(O)C3)c(OCC3CC3)n2)no1
Temperature: 100 °C
Yield: 54.3 %

Procedure:
5-Bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid [1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-amide (150 mg, 380 μmol) was dissolved in toluene (6.0 mL) to give a colorless solution. This solution was degassed under an Argon stream for 5 minutes. Cesium carbonate (371 mg, 1.14 mmol), Pd2(dba)3CHCl3 (39.3 mg, 38.0 μmol), [rac]-BINAP (47.3 mg, 75.9 μmol) and 3-azetidinol hydrochloride (1:1) (CAN 18621-18-6; 49.9 mg, 455 μmol) were added and the mixture was heated for 18 hours in a microwave oven to 100° C. After cooling to room temperature the mixture was diluted with ethyl acetate (5 mL) and water (3 mL), filtered through Celite® and the filter pad was washed with water (10 mL) and ethyl acetate (30 mL). Phases were separated and the aqueous phase was extracted with ethyl acetate (20 mL). Organic phases were combined, dried with Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography (silica gel. 20 g, 0% to 100% ethyl acetate in heptane) to give the title compound (80 mg, 54%) as yellow solid; NMR complies.
Reaction SMILES: [C:1]([CH:3]=[CH:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[CH:19]([F:21])[F:20])#[N:2].[NH:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([CH2:3][CH:4]([N:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8][CH:7]1[CH:19]([F:21])[F:20])#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCN(CC=CC#N)C(C(F)F)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C(C(F)F)C1
Reaction time: 4.5 h
Yield: 52.7 %

Procedure:
A mixture of tert-butyl 4-[3-cyanoprop-2-en-1-yl]-3-(difluoromethyl)piperazine-1-carboxylate (0.12 g, 0.40 mmol from Step 5) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.12 g, 0.40 mmol, prepared as described in WO 2007/070514, Example 65) and potassium carbonate (0.16 g, 1.2 mmol) in DMF (0.36 mL) was stirred for 4.5 h. The mixture was then filtered, the filtrate was diluted with EtOAc, washed with water (thrice), brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography on a 40 g silica gel cartridge eluting with a gradient of 0-80% solvent mixture [A] in hexanes ([A]=10% IPA: 50% EtOAc: 40% Hexanes) afforded a purified product (130 mg, 53%). 1H NMR (300 MHz, CDCl3): δ 8.83 (s, 2H), 8.33-8.28 (m, 4H), 7.42-7.38 (d, 2H), 6.79-6.76 (d, 2H), 5.89 (td, 1H), 5.63 (td, 1H), 5.67 (s, 4H), 4.57 (tt, 2H), 4.18-1.10 (m, 26H), 1.45, 1.43, 1.40 (3s, together 18H), 0.92 (dd, 4H), −0.08 (s, 18H); LCMS (M+H)+: 617.3.
Reaction SMILES: [O:1]=[C:2]1[C:7]2=[C:8]([S:15]([NH2:18])(=[O:17])=[O:16])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][O:3]1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([NH:29][C:30](=O)[O:31]C2C=CC=CC=2)[N:22]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C.O>[CH3:28][O:27][C:25]1[CH:26]=[C:21]([O:20][CH3:19])[N:22]=[C:23]([NH:29][C:30]([NH:18][S:15]([C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]3[CH2:5][CH2:4][O:3][C:2](=[O:1])[C:7]=23)(=[O:17])=[O:16])=[O:31])[N:24]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: NS(=O)(=O)c1c2n(c3ccccc13)CCOC2=O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2c3n(c4ccccc24)CCOC3=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 60 mg (0.23 mmol) sample of 3,4-dihydro-1-oxo-1H-[1,4]oxazino[4,3-a]indole-10-sulfonamide was dissolved in 1 mL dry acetonitrile and 70 mg (0.27 mmol) of phenyl (4,6-dimethoxypyrimidin-2-yl)carbamate was added. To this was added 0.040 mL of DBU and the mixture was stirred at room temperature for 30 minutes. A 0.2N solution of HCl was then added until the pH of the mixture was less than 2. Additional water was added and the resulting precipitate was collected by filtration and rinsed with water, then ethyl ether to afford 70 mg of the title compound, m.p. 206°-210° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:32])[CH:5]=[C:6]([Cl:31])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:30])[CH2:22][C:23]1[S:24][C:25]([CH2:28][OH:29])=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[Cl:31][C:6]1[CH:5]=[N+:4]([O-:32])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21](=[O:30])[CH2:22][C:23]1[S:24][C:25]([CH:28]=[O:29])=[CH:26][CH:27]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)Cc2ccc(CO)s2)cc1OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)Cc2ccc(C=O)s2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]2-[5-(hydroxymethyl)-2-thienyl]acetate (100 mg, 0.20 mmol) in dichloromethane (2 mL) was added Dess-Martin periodinane (102 mg, 0.24 mmol) at −78° C. The reaction was stirred at room temperature for 30 min. The reaction solution was washed with saturated aqueous Na2S2O3 (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The organic phase was passed through a hydrophobic fit and concentrated in vacuo to give the title compound as a pale yellow oil (100 mg, quantitative yield) which was used in the next step without further purification.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:39][C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][CH:36]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1cccc(Cl)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1cccc(Cl)c1

Procedure:
Compound 64 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-chloro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound. LC/MS [357 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.20 (br s, 1H), 9.00 (d, 1H), 8.55 (s, 1H), 8.39 (d, 1H), 8.20 (s, 1H), 7.56 (m, 1H), 7.47-7.26 (m, 3H), 5.48 (s, 1H), 3.16 (dd, 1H), 2.92 (dd, 1H), 2.31 (s, 3H)
Reaction SMILES: [CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCc1csc(NC2CCCCC2)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1csc(NC2CCCCC2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 10 g of 2-cyclohexylaminothiazol-4-ylmethanol, 22.4 g of sulfur trioxide pyridine complex, 14.3 g of triethylamine and 100 ml of dimethyl sulfoxide, giving the title compound as a pale brown oil.
Reaction SMILES: [CH3:1][Li].[C:3]([C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:14][CH:15]=[CH2:16])[CH2:9][CH2:10][C:11](Cl)=[O:12])([O:5][CH2:6][CH3:7])=[O:4].[Cl-].[NH4+]>[Cu](I)I.CCOCC>[C:3]([C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:14][CH:15]=[CH2:16])[CH2:9][CH2:10][C:11](=[O:12])[CH3:1])([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=CCC(CCC(=O)Cl)(C(=O)OCC)C(=O)OCC
Reactant: [Li]C
Agent: I[Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC(CCC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 6 h
Yield: 109.1 %

Procedure:
To an ether suspension (2 ml) containing copper iodide (0.293 g, 1.2 mmol) was added dropwise at −10° C. 1.26 ml of 1.91M ether solution containing methyl lithium (2.4 mmol). After heating to 0° C. over 30 minutes, the reaction liquid was given 4,4-dicarboethoxy-6-heptenic acid chloride (0.291 g, 1.0 mmol), followed by stirring at 0° C. for 6 hours. After addition of a saturated aqueous solution of ammonium chloride, the reaction liquid was extracted with ether. The organic layer was dried with anhydrous magnesium sulfate and freed of solvent by vacuum distillation. The residues were purified by silica gel chromatography to give 0.295 g of 5,5-dicarboethoxy-7-octen-2-on (yields: 91%). Characteristic Values of 5,5-dicarboethoxy-7-octen-2-on
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH2:15]([O:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([C@H:30]3[CH2:32][C@H:31]3[CH2:33][CH2:34][OH:35])[CH2:26][CH2:25]2)=[N:22][CH:23]=1)[CH3:16].[Br:36][C:37]1[C:42]([F:43])=[CH:41][C:40](O)=[CH:39][C:38]=1[F:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:36][C:37]1[C:42]([F:43])=[CH:41][C:40]([O:35][CH2:34][CH2:33][C@@H:31]2[CH2:32][C@@H:30]2[CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[N:22]=[CH:23][C:18]([O:17][CH2:15][CH3:16])=[CH:19][N:20]=3)[CH2:29][CH2:28]2)=[CH:39][C:38]=1[F:45]
Reactant: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Reactant: Oc1cc(F)c(Br)c(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(Br)c(F)c3)CC2)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
DIAD (2.45 mL, 12.6 mmol) was slowly added to a solution of 2-((1S,2R)-2-(1-(5-ethoxypyrimidin-2-yl)piperidin-4-yl)cyclopropyl)ethanol (2.45 g, 8.41 mmol), 4-bromo-3,5-difluorophenol (1.93 g, 9.25 mmol), and triphenylphosphine (3.31 g, 12.6 mmol) in DCM (30 mL) that had been cooled to 0° C. The ice bath was removed and the resulting mixture was stirred at rt for 3 hrs. The reaction mixture was diluted with DCM (20 mL) and washed with a 2 N NaOH solution (30 mL×1). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (KP-Sil 100 g SNAP column, Biotage system) eluting with 5-40% EtOAc:hexanes over 12 CV to afford the title compound. LC/MS (m/z): 482 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][S:10][C:6]=2[C:5]([C:12]2[CH:13]=[C:14]([CH2:18]O)[CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.O=S(Cl)[Cl:22]>C(Cl)(Cl)Cl>[Br:11][C:8]1[C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][Cl:22])[CH:13]=3)[C:6]=2[S:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1ncc(-c2cccc(CO)c2)c2scc(Br)c12
Solvent: ClC(Cl)Cl
Product: Nc1ncc(-c2cccc(CCl)c2)c2scc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of example 673A (550 mg, 1.64 mmol) in CHCl3 (5 mL) was treated with SOCl2 (5 mL), stirred at room temperature for 3 hours then concentrated to give the title compound. MS (ESI (+)) m/e 352.7, 354.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]5=[CH:34][C:35]([C:37]6[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=6)=[CH:36][N:32]5[N:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:43][Mg]Br.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][S@:10]([C:12]([CH3:13])([CH3:14])[CH3:15])=[O:11])([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[C:33]5=[CH:34][C:35]([C:37]6[CH:38]=[N:39][N:40]([CH3:42])[CH:41]=6)=[CH:36][N:32]5[N:31]=[CH:30][N:29]=4)[CH2:24][CH2:23]3)=[N:20][CH:21]=2)[CH3:43])=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2cc3c(N4CCN(c5ncc(/C(=N\[S@@](=O)C(C)(C)C)c6ccc(F)cc6)cn5)CC4)ncnn3c2)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc3c(N4CCN(c5ncc(C(C)(N[S@@](=O)C(C)(C)C)c6ccc(F)cc6)cn5)CC4)ncnn3c2)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.4 %

Procedure:
(S,Z)—N-((4-Fluorophenyl)(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)methylene)-2-methylpropane-2-sulfinamide (190 mg, 0.324 mmol) was taken up in THF (3 mL) and cooled to 0° C. Methylmagnesium bromide (3 M solution in diethyl ether, 0.50 mL, 1.500 mmol) was added and the resulting mixture stirred at 0° C. for 45 minutes. Additional methylmagnesium bromide (3 M solution in diethyl ether, 0.10 mL, 0.300 mmol) was added and stirring at 0° C. continued for 20 minutes. Saturated ammonium chloride was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo while loading onto Celite. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave (S)—N-(1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (120 mg, 0.199 mmol, 61.5% yield) as a yellow solid (mixture of diastereoisomers). MS (ES+) C30H35FN10OS requires: 602. found: 603 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Br)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1cccc(O)c1
Reactant: BrCCc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCc2ccccc2)c1

Procedure:
Alkylation of 3-hydroxybenzaldehyde with phenethyl bromide was done following the method used in Example 34, except that DMF was used as the reaction solvent, to give 3-phenethoxybenzaldehyde as a clear oil. Yield (0.98 g, 54%): 1H NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 7.21-7.48 (m, 8H), 7.18-7.20 (m, 1H), 4.24 (t, J=7.0 Hz, 2H), 3.13 (t, J=7.0 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][C:20]([O:22]CC)=[O:21])=[O:16])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[S:3].[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[NH2:1][C:2]([NH:4][C:5]1[CH:6]=[C:7]([C:11]([NH:13][CH2:14][C:15]([NH:17][CH:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[S:3]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(N)=S)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: NC(=S)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Yield: 920 %

Procedure:
The product of Example 116 (500 mg, 0.095 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (350 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.ClC1C2C(=CC(OC)=CC=2)N=CC=1C(OCC)=O>CCOC(C)=O.C(O)C.[Pd]>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Agent: [Pd]
Agent: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Reaction time: 8 h
Yield: 89 %

Procedure:
Ethyl 7-methoxyquinoline-3-carboxylate. To a solution of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate (1.24 g, 4.67 mmol) in a mixture of EtOAc (30 mL) and ethanol (30 mL) was added 10% Pd/C (10 mg). The flask was evacuated and filled with nitrogen three times and evacuated and filled with hydrogen three times and stirred overnight. After filtration through a plug of silica the reaction mixture was concentrated onto silica. Purification by FCC (SiO2, 0-10% MeOH/DCM) afforded the title compound as a brown solid (955 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 9.37 (d, J=2.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 7.80 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 4.45 (q, J=7.0 Hz, 2H), 4.01-3.93 (m, 3H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=232.2.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>CO>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(Cc1ccc(CN2CCOCC2)cc1)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.8 %

Procedure:
Using General Procedure A: To a stirred solution of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (0.285 g, 0.72 mmol) in dry MeOH (5 mL) was added morpholine (0.068 mL, 0.78 mmol) and sodium cyanoborohydride (0.107 g, 1.7 mmol) and the mixture stirred at room temperature for 24 h. Purification of the crude product by radial chromatography on a 2 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 100:1:1) afforded the desired product (23 mg, 7%) as a colourless oil.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[C:12](Cl)(=[O:14])[CH3:13].Cl>ClC(Cl)C>[CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[C:12](=[O:14])[CH3:13])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1cc2ccccc2s1
Agent: Cl
Solvent: CC(Cl)Cl
Product: CCc1sc2ccccc2c1C(C)=O
Reaction time: 14 h
Yield: 765 %

Procedure:
Into a one-litre flask fitted with a mechanical stirrer and a dropping-funnel, 32.45 g (0.2 mol) of 2-ethyl-benzo[b]thiophene and 14.3 ml of acetyl chloride were introduced with 400 ml of dichloroethane. After the solution was cooled to between 5 and 10° C by means of an ice-bath, 23.2 ml (0.2 mol) of stannic chloride were introduced through the dropping-funnel. The mixture was then allowed to return to room temperature and was stirred for about 14 hours. The complex so formed was then hydrolysed with diluted hydrochloric acid. The organic and aqueous phases were separated by decantation and the aqueous phase was extracted with ether. The ethereal fraction was then added to the organic phase and the mixture was washed with water and evaporated to dryness to give, after distillation between 124°-134° C (0.01 mm/Hg), 31.3 g of 2-ethyl-3-acetyl-benzo[b]thiophene. Yield 765%.