Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:22](=O)[C:21]2[C:20]([C:24]([O:26]C)=O)=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][CH:14]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:35][NH2:36]>CO>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:13]1[C:22]2=[N:35][NH:36][C:24](=[O:26])[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([C:21]=32)[NH:15][CH:14]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1nccn1Cc1ccccc1)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1nccn1Cc1ccccc1
Yield: 27 %

Procedure:
Methyl 3-(1-benzyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (3.7 g, 8.46 mmol) in hydrazine monohydrate (25 mL) and methanol (100 mL) was stirred at room temperature for 5 h. The resulting mixture was filtered to give 9-(1-benzyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (950 mg, yield 27%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.61-4.64 (d, J=11.2 Hz, 1H), 4.99-5.12 (m, 1H), 6.83-6.89 (m, 4H), 7.14-7.28 (m, 1H), 7.36-7.38 (d, J=7.6 Hz, 1H), 7.54-7.58 (t, J=8.0 Hz, 7H), 12.20 (s, 1H). LC-MS (ESI) m/z: 420 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[CH:6][C:7]=1[CH3:8].[BrH:10].N([O-])=O.[Na+]>O.[Cu](Br)Br>[Br:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=1
Reactant: Cc1ccc(N)cc1I
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Br)cc1I
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
A mixture of 3-iodo-4-methyl-phenylamine (5.0 g, 21 mmol) and 48% hydrobromic acid (30 ml) was heated at 90° C. for 30 minutes. After cooling in an ice bath, a solution of sodium nitrite (1.7 g, 25.2 mmol) in water (5 ml) was added and stirred for 15 minute. This mixture was added to a mixture of copper bromide (I) (3.6 g, 25.2 mmol), 48% hydrobromic acid (20 ml) and ice (50 g) cooled in an ice bath. After stirring for 20 minutes, the mixture was heated at 90° C. for 1 hour. After stirring at room temperature for 16 hours, the mixture was treated with water (350 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 ml), washed with saturated aqueous sodium chloride solution (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with hexane to give 5-bromo-2-methyl-1-iodo-benzene (4.4 g, 71% yield). 1H NMR (acetone-d6) δ 2.40 (s, 3H, CH3), 7.30 (d, 1H, J=8.2 Hz, Ar), 7.50 (dd, 1H, J=8.2 Hz, J=2.0 Hz, Ar), 8.00 (d, 1H, J=2.0 Hz, Ar).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:30]([CH2:29][CH2:28][CH2:27][Cl:26])(=[O:32])=[O:31])[CH2:24][CH2:25]2)[N:3]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Temperature: 5 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (290 mg, 0.72 mmol, Example 59 and 3-chloropropanesulfonyl chloride (165 mg, 0.93 mmol, Aldrich) was treated with diisopropylethyl amine (102 mg, 102 mmol, Aldrich) in methylene chloride (200 mL). This was stirred for 1 hour at 5° C. The reaction was washed with 5% aqueous sodium bicarbonate, dried (MgSO4), and the solvent concentrated in vacuum. This solid was dissolved in tetrahydrofuran, filtered through celite, reduced in volume and triturated with ether to give 300 mg (82%) of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid. HRMS, observed: 486.1375; Calcd for (M+H)+: 486.1373
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.4 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (61 mg, 51%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH3:3].Br[C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1>>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:17]1[S:21][C:20]([NH2:22])=[N:19][N:18]=1)[CH3:3]
Reactant: Nc1nnc(Br)s1
Reactant: CN(C)Cc1cccc(OCCCN)c1
Product: CN(C)Cc1cccc(OCCCNc2nnc(N)s2)c1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(dimethylamino)methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2amine.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:26]=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:8]=2[C:27]2[N:31](COCC[Si](C)(C)C)[N:30]=[CH:29][CH:28]=2)[CH2:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:26]=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)=[O:12])=[CH:9][C:8]=2[C:27]2[NH:31][N:30]=[CH:29][CH:28]=2)[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)ccc1N1CC[C@@H](O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
(R)-4-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzamide (Stage 1.1, 149 mg, 0.2 mmol) was added to a MW vial, which was sealed and flushed with argon. A solution of 1 M TBAF in THF (2.98 mL, 2.98 mmol) was then added and the RM was stirred at 80° C. for 3 days. The RM was diluted with EtOAc (40 mL), washed with sat. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude product was purified by preparative SFC (Column DEAP, from 25% to 30% in 6 min) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=433.3 [M+H]+, m/z=431.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.75 (br. s, 1H) 1.86 (br. s, 1H) 2.70-2.79 (m, 1H) 3.03-3.19 (m, 2H) 3.19-3.28 (m, 1H) 4.20 (br. s, 1H) 4.73-4.92 (m, 1H) 6.34 (d, J=11.00 Hz, 1H) 6.73-6.94 (m, 1H) 7.32 (d, J=8.80 Hz, 2H) 7.65 (d, J=104.42 Hz, 1H) 7.81-7.96 (m, 4H) 10.10 (s, 1H) 12.88 (d, J=81.67 Hz, 1H).
Reaction SMILES: [H][H].[OH:3][C:4]1[C:25]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:5]=1[C:6](=[O:21])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][O:19][CH3:20])[CH:10]=1>[Pd].C(OCC)(=O)C>[OH:3][C:4]1[C:25]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:24]([O:31][CH3:32])[CH:23]=[C:22]([O:33][CH3:34])[C:5]=1[C:6](=[O:21])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][O:19][CH3:20])[CH:10]=1
Reactant: COCOc1cc(C=CC(=O)c2c(OC)cc(OC)c(CC=C(C)C)c2O)ccc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCOc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)ccc1OC
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To 40 ml of an ethyl acetate solution of 0.7 g of 5% palladium/carbon, in which hydrogen had been adsorbed in advance, was added 160 ml of an ethyl acetate solution of 5.0 g of the so-obtained 2'-hydroxy-4,4',6'-trimethoxy-3-methoxymethoxy-3'-(3-methyl-2-butenyl)chalcone, and hydrogen was further adsorbed with strong stirring. Then the mixture was stirred overnight, and the palladium/carbon was removed by using Celite and the solvent was removed by distillation. The residue was dissolved in diethyl ether and crystallized by addition of hexane to obtain 4.4 g (yield=91%) of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-methoxy-3-methoxymethoxyphenyl)-1-propanone in the form of a white solid.
Reaction SMILES: C(O)C.Br[C:5]1[CH:6]=[C:7]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:8]2[CH:9]=[CH:10][N:11]([CH:14]([CH3:16])[CH3:15])[C:12]=2[CH:13]=1>[Pd].O1CCCC1>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:17]([C:7]1[C:8]2[CH:9]=[CH:10][N:11]([CH:14]([CH3:16])[CH3:15])[C:12]=2[CH:13]=[CH:5][CH:6]=1)=[O:18]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2ccn3C(C)C)c(=O)[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cccc3c2ccn3C(C)C)c(=O)[nH]1
Yield: 60.2 %

Procedure:
To a flask under N2 atmosphere was added 10% palladium on carbon (0.028 g, 0.026 mmol) and ethanol (1 mL) (to wet catalyst). The flask was then charged with 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (0.11 g, 0.264 mmol), ethanol (4 mL) and tetrahydrofuran (1 mL). The suspension was stirred under N2, then evacuated and refilled with H2 (balloon) and stirred overnight. The reaction was then placed back under N2 and diluted with 10% methanol/dichloromethane. Celite was added and the mixture was stirred for 15 min, filtered through a pad of Celite, washed with 10% methanol/dichloromethane, and concentrated. The residue was dissolved in dimethylsulfoxide and acetonitrile (with 0.1% trifluoroacetic acid and purified by Gilson prep HPLC (Sunfire 30×75 mm; Gradient B: 15-75%; A: water+0.1% TFA; B: acetonitrile+0.1% TFA). The resulting residue was dissolved in 10% methanol/dichloromethane and treated with Silicycle carbonate resin (1.5 g). The mixture was stirred for 30 min, filtered through Celite, washed with 10% methanol/dichloromethane, and concentrated. The residue was dissolved in dichloromethane and treated with methyl-t-butylether. The solvents were removed by via N2 stream and the solids dried in a vacuum oven at 45° C. for 18 h to give N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indole-4-carboxamide (56 mg, 0.159 mmol, 60% yield). 1 H NMR (400 Hz, DMSO-d6) δ ppm 1.41-1.48 (m, 6 H) 2.09-2.15 (m, 3 H) 2.24 (s, 3 H) 4.35 (d, J=5.31 Hz, 2 H) 4.79 (quin, J=6.63 Hz, 1 H) 5.88 (s, 1 H) 6.84 (d, J=3.03 Hz, 1 H) 7.11-7.18 (m, 1 H) 7.39 (d, J=6.57 Hz, 1 H) 7.58 (d, J=3.28 Hz, 1 H) 7.65 (d, J=8.34 Hz, 1 H) 8.08 (t, J=5.31 Hz, 1 H) 11.54 (br. s., 1 H). MS (ES) [M+H]+ 338.6.
Reaction SMILES: [Na].[CH2:2]1[O:10][C:9]2[CH:8]=[CH:7][C:6]([OH:11])=[CH:5][C:4]=2[O:3]1.[Br:12][CH2:13][CH:14]=[CH:15][CH2:16]Br>COCCOC>[Br:12][CH2:13][CH:14]=[CH:15][CH2:16][O:11][C:6]1[CH:7]=[CH:8][C:9]2[O:10][CH2:2][O:3][C:4]=2[CH:5]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: BrCC=CCBr
Agent: [Na]
Solvent: COCCOC
Product: BrCC=CCOc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6.4 g (0.04 mol) of sodium salt of 3,4-methylendioxyphenol are added at -20° to a solution of 8.6 g (0.04 mol) of 1,4-dibromo-2-butene in 100 cc of 1,2-dimethoxyethane. The mixture is stirred at 0° for 3 hours and subsequently at room temperature for 1 hour. The solvent is distilled off at reduced pressure and the residue is taken up in ether. The ether solution is extracted with saturated salt solution, is dried with sodium sulphate and evaporated. The residue is purified by chromatography on silica gel with hexane/ethyl acetate 9:1. The 5-(4-bromo-2-butenyloxy)-1,3-benzodioxol is obtained as colourless oil.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[SH:25])[C@@H:20]([NH:26][C:27](=[O:57])/[C:28](/[C:50]2[N:51]=[C:52]([NH2:56])[S:53][C:54]=2[Cl:55])=[N:29]\[O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]3=[O:58])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:59]([O:63][C:64]([NH:66][CH2:67][CH2:68][S:69][CH2:70][C:71]1[CH:72]=[N:73][CH:74]=[CH:75][C:76]=1Cl)=[O:65])([CH3:62])([CH3:61])[CH3:60].O>CN(C)C=O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[CH:21]([CH2:22][CH2:23][C:24]=2[S:25][C:76]2[CH:75]=[CH:74][N:73]=[CH:72][C:71]=2[CH2:70][S:69][CH2:68][CH2:67][NH:66][C:64]([O:63][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:65])[C@@H:20]([NH:26][C:27](=[O:57])/[C:28](/[C:50]2[N:51]=[C:52]([NH2:56])[S:53][C:54]=2[Cl:55])=[N:29]\[O:30][C:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:19]3=[O:58])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(S)CCC23)c(Cl)s1
Reactant: CC(C)(C)OC(=O)NCCSCc1cnccc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSCc1cnccc1SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3nc(N)sc3Cl)C2CC1
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(triphenylmethoxyimino]-acetamido]-3-mercapto-8-oxo-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate diphenylmethyl ester (3.0 g, 0.0036 mol) in dimethylformamide (30 mL) was added 3-(N-tert-butoxycarbonylaminoethylthiomethyl)-4-chloropyridine (1.3 g, 0.0043 mol) at room temperature. After stirring overnight, the reaction mixture was treated with water (200 mL), and the solid that formed was filtered and dried to afford the crude title compound (2.9 g).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:31]1([CH2:37]Br)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCC1CCCCC1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2CC2CCCCC2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and cyclohexylmethyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.43 (m, 1 H), 7.21-7.12 (m, 2 H), 7.00-6.93 (m, 1 H), 6.37 (dd, J=3.4, 7.3 Hz, 1 H), 5.52 (br. s., 1 H), 4.39-4.27 (m, 3 H), 4.25-4.14 (m, 1 H), 2.98-2.77 (m, 5 H), 2.17-2.04 (m, 2 H), 1.96 (td, J=3.7, 7.2 Hz, 1 H), 1.78-1.56 (m, 5 H), 1.31-1.15 (m, 3 H), 0.95 (s, 9 H); LC/MS (m/z) ES+=491.47 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[O:10][CH3:11].ClC1C=CC(C)=C(OC)C=1.C1C(=O)[N:26](Br)[C:24](=O)C1>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:9][C:5]1[C:4]([O:10][CH3:11])=[C:3]([CH2:2][CH2:24][NH2:26])[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(Cl)cccc1CBr
Agent: COc1cc(Cl)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cccc1CCN
Temperature: 25 °C

Procedure:
1-(bromomethyl)-3-chloro-2-methoxybenzene. A mixture of 4-chloro-2-methoxy-1-methylbenzene (26.5 g, 169 mmol), NBS (33.1 g, 186 mmol) and benzoyl peroxide (200 mg, 0.826 mmol) in CHCl3 was heated to reflux for 24 h. The reaction was allowed to cool to RT and then concentrated in vacuo. The residue was stirred with petroleum ether and the resulting suspension was filtered off and the filtrate was concentrated in vacuo to give the title compound (30.9 g) as brown oil, which was used as it is in the next step. UPLC (2 min) rt 1.708 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35].CC(C)=O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:37][S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])(=[O:35])=[O:36])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4]
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)Cl)cc1OC)cn2C
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Temperature: 15 °C
Yield: 96.4 %

Procedure:
A solution of 4-(dimethylamino)pyridine (8.17 g, 66.9 mmole) in dichloromethane (20 ml) was added over 15 minutes to a stirred suspension of the product of step c) (9.94 g, 26.8 mmole) and 2-methylbenzenesulfonamide (6.87 g, 40.1 mmole) in dichloromethane (30 ml). After 45 minutes the solution was heated to reflux and 20 ml distillate collected. Acetone (150 ml) was added and a further 80 ml distillate collected. The mixture was allowed to cool overnight and finally stirred at 15° C. before collection of the solid by filtration. This was then slurry-washed with methanol (3×30 ml) to afford 16.22 g (96.4%) of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide, as its 4-(dimethylamino)pyridine salt; m.p. 185°-187° C. (with partial melting and resolidification at 138°-140° C.); NMR (250 MHz, DMSO-d6): 2.53 (s, 3H, ArCH3), 3.13 (s, 6H, N(CH3)2), 3.76, 3.83, 3.86 (each s, 3H, OCH3 plus NCH3 plus CO2CH3), 4.02 (s, 2H, ArCH2Ar'), 6.92 (d, 2H), 7.02 (d, 1H), 7.11-7.32 (m, 4H), 7.39-7.53 (m, 3H), 7.75 (dd, 1H), 7.88 (d, 1H), 8.20 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>>[C:7]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)(=[O:9])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c[nH]cn1
Product: CC(=O)n1cnc(C)c1
Yield: 68.9 %

Procedure:
The 1-Acetyl-4-methylimidazole intermediate was prepared by making a mixture of 4-methylimidazole (82.1 g, 1.0 mol)) and acetic anhydride (190 mL, 2.0 mol) and refluxing for 15 min after which time 150 mL of solvent was removed by distillation at atmospheric pressure (head temperature 125° C.) over a 1 h period. The remaining acetic anhydride was removed at 50° C./0.5 mm and the residual liquid was crystallized from ether (150 mL) at -20° C. to give 85.5 g of 1-acetyl-4-methylimidazole product, m.p. 49°-51° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH2:22])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:4][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:14][C:15]=2[C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2nc(NC(=O)c3ccccc3)sc2-c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 65.7 %

Procedure:
To a solution of [4-[4-(1,1-Dimethylethyl)phenyl]-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.62 mmol) and 4-dimethylaminopyridine (0.05 g, 0.39 mmol) in N,N-dimethylacetamide (5 mL) was added benzoyl chloride (0.15 g, 1.94 mmol), and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured an aqueous sodium hydrogencarbonate and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.44 g, yield 66%).
Reaction SMILES: [O:1]([C@@H:9]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][OH:21])=[CH:18][C:13]=2[O:12][CH2:11][C@H:10]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:61]1[CH:62]=[C:63]([CH:69]=[CH:70][CH:71]=1)[C:64]([O:66][CH2:67][CH3:68])=[O:65]>O1CCCC1>[O:1]([C@@H:9]1[C:14]2[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][O:21][C:70]3[CH:71]=[CH:61][CH:62]=[C:63]([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH:69]=3)=[CH:18][C:13]=2[O:12][CH2:11][C@H:10]1[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1c2ccc(CCO)cc2OC[C@H]1Cc1ccccc1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OCCc2ccc3c(c2)OC[C@@H](Cc2ccccc2)[C@@H]3O[Si](C)(C)C(C)(C)C)c1
Yield: 18.9 %

Procedure:
To a stirred solution of the compound of step A (720 mg, 18 mmole) in tetrahydrofuran (10 ml) was added diethylazodicarboxylate (430 μl, 2.5 mmole), triphenylphosphine (710 mg, 2.5 mmole) and ethyl 3-hydroxybenzoate (415 mg, 2.5 mmole). The mixture was refluxed for 3 days, the solvent removed in vacuo and the residue chromatographed (silica gel, 3:1 hexane:ether) to afford 258 mg of the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20]([C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[O:32][CH3:33])=S)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:41]#[C:42][NH2:43]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20](=[N:43][C:42]#[N:41])[C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=2[O:32][CH3:33])[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(F)(F)F)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Reactant: N#CN
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C(F)(F)F)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Yield: 89.5 %

Procedure:
The product of Example 34C (0.97 g, 1.9 mmol), triethylamine (1.1 mL, 7.8 mmol), cyanamide (0.25 g, 5.8 mmol) and Hg(OAc)2 (1.2 g, 3.9 mmol) in acetonitrile (15 mL) were processed as described in Example 16E to provide the title compound (0.84 g, 1.7 mmol, 85% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H), 1.73-1.86 (m, 1H), 1.85-1.98 (m, 1H), 2.01 (s, 3H), 2.21-2.48 (m, 4H), 3.98 (s, 3H), 4.77 (s, 2H), 6.63 (s, 1H), 7.09 (d, J=8.5 Hz, 1H), 7.60-7.71 (m, 2H); MS (DCI/NH3) m/z 509 (M+H)+. Anal. calculated for C24H27F3N4O3S; C, 56.68; H, 5.35; N, 11.02. Found: C, 56.50; H, 5.10; N, 10.67.