Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S1CCCC1.[Cl-].C([S+]1CCCC1)C1C=CC=CC=1.[OH-].[K+].[C:29]1(=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CO.O>[C:2]1([CH:1]2[C:29]3([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[O:35]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: ClCc1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCSC1
Solvent: O
Product: c1ccc(C2OC23CCCCC3)cc1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
A mixture of 152 g (1.18 mol) of benzyl chloride, 108 g (1.18 mol) of tetrahydrothiophene and 0.225 L of water is stirred well at 85° C. until a homogeneous clear or slightly turbid single-phase solution of S-benzyltetrahydrothiophenium chloride has been obtained. The solution is cooled to 20° C. and is slowly added dropwise to a reaction mixture consisting of potassium hydroxide solution (prepared from 267 g (4.75 mol) of potassium hydroxide in 0.53 L of ice-water) and 467 g of cyclohexanone (4.75 mol) in 225 g of methanol. After the addition is complete, the reaction mixture is allowed to stand for 10 minutes until the phases have separated; the organic phase is separated off and subjected to fractional distillation. 181 g (80%) of 2-phenyl-1-oxa-spiro[2.5]octane are obtained in the form of a clear colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[S:22][C:21]([C:23]3([OH:27])[CH2:26][CH2:25][CH2:24]3)=[N:20][CH:19]=2)[CH:14]=[C:15]([CH3:17])[CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:17][C:15]1[CH:14]=[C:13]([C:18]2[S:22][C:21]([C:23]3([OH:27])[CH2:26][CH2:25][CH2:24]3)=[N:20][CH:19]=2)[CH:12]=[C:11]([NH:10][C:2]2[N:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=1
Reactant: CSc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(-c2cnc(C3(O)CCC3)s2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CSc1ccnc(Nc2cc(C)cc(-c3cnc(C4(O)CCC4)s3)c2)n1
Temperature: 85 °C
Yield: 92 %

Procedure:
To a mixture of 2-chloro-4-(methylsulfanyl)pyrimidine (Intermediate 28, 500 mg, 3.11 mmol) and Intermediate 15 (810 mg, 3.11 mmol) in dioxane (15 mL) was added palladium(II) acetate (70 mg, 0.311 mmol), XantPhos (270 mg, 0.467 mmol) and cesium carbonate (2 g, 6.23 mmol). The mixture was degassed for 10 min and then heated at 85° C. for 16 h. After cooling to ambient temperature, the reaction mixture was filtered over celite and was washed with DCM/MeOH. After solvent removal, the residue was purified by column chromatography on silica gel (10 to 100% 10:1 ethyl acetate: methanol in hexanes) to afford 1-[5-(3-methyl-5-{[4-(methylsulfanyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutanol (1.1 g, 2.86 mmol, 92%). MS ESI: [M+H]+ m/z 385.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:45])[O:14][CH2:15][C@@H:16]([N:31]([CH3:44])[C:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[Cl:43])=[O:33])[CH2:17][CH2:18][CH2:19][N:20]1C(=O)C3C(=CC=CC=3)C1=O)=[CH:5]2.NN>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:45])[O:14][CH2:15][C@@H:16]([N:31]([CH3:44])[C:32]([NH:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[C:37]=1[Cl:43])=[O:33])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN1C(=O)c2ccccc2C1=O)COC(=O)Nc1cc2cc(F)ccc2cn1
Agent: NN
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(1,3-dioxoisoindolin-2-yl)pentyl 6-fluoroisoquinolin-3-ylcarbamate (400 mg, 0.64 mmol) in MeOH (10.0 mL) was added NH2NH2 (1.0 mL). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated and re-dissolved in MeOH. The resulting solution was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (305 mg, quant.). LRMS (M+H+) m/z 506.2.
Reaction SMILES: C(OC([NH:6][CH:7]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]([CH2:24][C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[C:8]1=[O:31])=O)C.Br>C(Cl)Cl>[NH2:6][CH:7]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[N:9]([CH2:24][C:25]([C:27]([CH3:29])([CH3:28])[CH3:30])=[O:26])[C:8]1=[O:31]
Reactant: CCOC(=O)NC1N=C(c2ccccn2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O
Agent: Br
Solvent: ClCCl
Product: CC(C)(C)C(=O)CN1C(=O)C(N)N=C(c2ccccn2)c2ccccc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 90.6 %

Procedure:
(3RS)-Ethyloxycarbonylamino-1-(tert-butylcarbonylmethyl)-2,3-dihydro-5-(2-pyridyl)-1H-1,4-benzodiazepin-2-one (IV, 250 mg, 0.592 mmol) was taken up in dry DCM (10 ml) at 0° C. and saturated with dry HBr gas. The mixture was stoppered and stirred at r.t. for 64 h. The solvent was evaporated and the product partitioned between 1M HCl and EtOAc. The acid portion was basified and extracted with CHCl3 (×3). The extracts were combined and washed with brine, dried and evaporated to give a brown foam (188 mg, 91%), which was not purified further.
Reaction SMILES: NC1C(C(OCC)=O)=NOC=1C1C=CC=C(/C=C/CO)C=1.[OH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29](O)[C:24]=1C(OC)=O.[CH:34]1[CH:39]=[CH:38][C:37]([P:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:36][CH:35]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:23]1([O-:22])[CH:32]=[CH:31][CH:30]=[CH:29][CH:24]=1.[CH:50]1[CH:49]=[CH:48][C:47]([P:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37]2[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=2)=[CH:52][CH:51]=1
Reactant: COC(=O)c1c(O)cccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)c1noc(-c2cccc(/C=C/CO)c2)c1N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [O-]c1ccccc1

Procedure:
To a THF (1 mL) solution of compound from Example 21D (150 mg, 0.52 mmol), methyl 2,6-dihydroxybenzoate (336 mg, 2.0 mmol), and PPh3 (210 mg, 0.8 mmol) was added DEAD (140 mg, 0.8 mmol) at 0° C. Insoluble salt (phenolate/PPh3) formed quickly. The mixture was warmed to ambient temperature and dichloromethane (3 mL) was added, but the salt remained insoluble in this solvent system. A drop of water was added after 2 hours to decompose the salt, upon which the slurry turned into a homogeneous solution. The mixture was purified by flash column chromatography (30% ethyl acetate in hexanes) to provide the titled compound (130 mg, 40%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[CH:23][C:22]=1[Cl:41])=[O:19])=[O:12].Cl>O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][C:22]=1[Cl:41])=[O:19])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)c3[nH]cnc3C(=O)Nc3nc4ccccc4[nH]3)c(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1nc2ccccc2[nH]1)c1nc[nH]c1C(=O)Nc1ccc(OC2CCNCC2)cc1Cl
Yield: 83 %

Procedure:
1-dimethylethyl 4-({4-[({4-[(1H-benzimidazol-2-ylamino)carbonyl]-1H-imidazol-5-yl}carbonyl)amino]-3-chlorophenyl}oxy)piperidine-1-carboxylate was treated with 4M hydrogen chloride in dioxane to give N4-1H-benzimidazol-2-yl-N5-[2-chloro-4-(piperidin-4-yloxy)phenyl]-1H-imidazole-4,5-dicarboxamide as its hydrochloride salt in 83% yield. 1H-NMR (400 MHz, DMSO-d6): 13.9 (s, br, 1H), 13.7 (s, 1H), 12.2 (s, 1H), 10.4 (s, 1H), 8.41-8.39 (m, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.45 (s, 2H), 7.07 (s, 2H). MS (EI): 450 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][CH:12]([C:18]([O:20][CH3:21])=[O:19])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(NN)(C1C=CC(C)=CC=1)(=O)=O.C([BH3-])#N.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:16][CH:14]([CH2:13][CH:12]([C:18]([O:20][CH3:21])=[O:19])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CC2CN(C(=O)OC(C)(C)C)CC(C1)C2=O
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CC2CC(C1)CN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of methyl 3-(tert-butoxycarbonyl)-9-oxo-3-azabicyclo[3.3.1]nonane-7-carboxylate (14.76 g, 49.63 mmol), in anhydrous THF (250 mL) was added tosylhydrazine (11.1 g, 59.6 mmol), and the mixture was stirred for 2 h at ambient temperature. The reaction mixture was heated to 65° C., sodium cyanoborohydride (12.5 g, 198 mmol) was added, and the mixture was stirred for 16 h at 65° C. The reaction mixture was cooled to ambient temperature and concentrated by rotary evaporation. The residue was purified by flash silica gel chromatography, using an ethyl acetate in hexane gradient, to give 8.71 g (61.9% yield) of the methyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylate as a colorless solid (1H NMR (CDCl3): δ 3.97-3.8 (m, 2H), 3.65 (s, 3H), 2.85-2.75 (m, 2H), 2.57-2.47 (m, 1H), 2.38-2.20 (m, 2H), 2.0-1.7 (m, 4H), 1.68-1.60 (m, 1H), 1.52-1.41 (m, 1H), 1.41 (s, 9H); LC-MS (MH+): 284).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:32]1[C:40]2[C:35](=[C:36](B3OC(C)(C)C(C)(C)O3)[C:37]([F:41])=[CH:38][CH:39]=2)[CH:34]=[CH:33]1)(C(C)(C)C)(C)C>>[F:41][C:37]1[C:36]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:35]2[C:40](=[CH:39][CH:38]=1)[NH:32][CH:33]=[CH:34]2
Reactant: Clc1nc(N2CCOCC2)c2nc(CC3CCOCC3)ccc2n1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: Fc1ccc2[nH]ccc2c1-c1nc(N2CCOCC2)c2nc(CC3CCOCC3)ccc2n1

Procedure:
4-(2-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (0.05 g) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 38.8 mg of 154 following reverse phase HPLC purification. MS (Q1) 448.2 (M)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25](Cl)(=[O:31])[O:26][CH2:27][CH:28]([CH3:30])[CH3:29]>>[CH3:29][CH:28]([CH3:30])[CH2:27][O:26][C:25](=[O:31])[NH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:4]=1
Reactant: CC(C)COC(=O)Cl
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: CC(C)COC(=O)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 42 and 2-methylpropyl carbonochloridate were treated using a method similar to that described in Example 128 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.59-11.61 (bs, 1H), 8.32 (dd, J=7.8, 1.4 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.96-8.02 (m, 1H), 7.88-7.94 (m, 1H), 7.65-7.75 (m, 1H), 7.36-7.45 (m, 4H), 4.50 (d, J=5.9 Hz, 2H), 3.77 (d, J=6.6 Hz, 2H), 3.67 (s, 2H), 1.73-1.89 (m, 1H), 0.67-0.68 (m, 6H); MS (ESI−) M/Z 441 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[N:14]=[C:13]3[C:26]2[N:27]=[N:28][N:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[O:38])=[CH:33][CH:32]=3)[CH:30]=2)[N:3]=1.[OH:45][C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.[F-].[Cs+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:45][C:46]1[CH:51]=[CH:50][C:49]([C:2]2[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH2:9][C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[C:26]3[N:27]=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)[CH:30]=3)[N:3]=2)=[CH:48][CH:47]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(Cn3nc(Cl)ccc3=O)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(Cn5nc(-c6ccc(O)cc6)ccc5=O)cc34)nn2)cc1)N1CCOCC1
Temperature: 120 °C
Yield: 12 %

Procedure:
A suspension of PdCl2(PPh3)2 (10 mg; 0.01 mmol; 0.11 eq.), tert-butyl 5-[(3-chloro-6-oxopyridazin-1(6H)-yl)methyl]-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-1-carboxylate (79 mg; 0.13 mmol; 1.0 eq.), 4-hydroxyphenylboronic acid (35 mg; 0.25 mmol; 2.0 eq.) and cesium fluoride (65 mg; 0.43 mmol; 3.3 eq.) in DMF (2.0 mL) and water (1.0 mL) was degassed with argon in a sealed tube and heated in MW at 120° C. for 1.5 h. The mixture was then filtered through a celite pad. The filtrate was diluted with EtOAc. The phases were separated and organic phase was washed with a 1 N solution of HCl, dried over magnesium sulfate, filtered and concentrated. Purification of the crude by preparative HPLC gave the title compound as a white solid (9 mg, 9%). 1H NMR (300 MHz, DMSO-d6) δ 13.40 (s, 1H), 9.85 (br, 1H), 9.38 (s, 1H), 8.46 (s, 1H), 8.18-8.12 (m, 2H), 7.98 (d, J=9.8 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.6 Hz, 1H), 7.54-7.46 (m, 1H), 7.05 (d, J=9.7 Hz, 1H), 6.85 (d, J=8.7 Hz, 2H), 5.46 (s, 2H), 3.75-3.43 (m, 8H). HPLC (max plot) 98.6%; Rt 3.14 min. UPLC/MS: (MS+) 575.1, (MS−) 573.0.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:36]([F:39])([F:38])[F:37])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:40][NH2:41]>>[F:29][C:28]([F:30])([F:31])[C:26]1[CH:27]=[C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:41][CH3:40])[CH2:17][C:16]=3[CH:18]=[C:19]([C:36]([F:39])([F:37])[F:38])[CH:20]=2)[CH:23]=[C:24]([C:32]([F:34])([F:33])[F:35])[CH:25]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3O2)cc1
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2O1

Procedure:
The title compound was prepared (0.033 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.070 g, 0.12 mmol) and methylamine (0.12 g, 3.9 mmol). mp 205-207° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].CC1(C)[O:24][CH:23]([CH2:25][NH2:26])[CH2:22][O:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:26][CH2:25][CH:23]([OH:24])[CH2:22][OH:21])=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: CC1(C)OCC(CN)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)NCC(O)CO)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (160 mg; 0.53 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 2,2-Dimethyl-1,3-dioxolane-4-methanamine (Aldrich) (0.07 ml; 0.53 mmol; 1 eq.) and triethylamine (0.15 ml; 1.06 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC. As some TFA is used for the mobile phase of the preparative HPLC, the diol protecting group is removed during the concentration of the chromatography fractions, affording directly Compound (39) as a white-off solid (26.6 mg; 14%). 1H NMR (DMSO-d6, 300 MHz) δ 2.15 (s, 3H), 2.49 (s, 3H), 3.17-3.52 (m, 4H), 3.67 (m, 1H), 4.65 (br s, 1H), 4.93 (br s, 1H), 7.99 (s, 1H), 8.46 (t, J=4.5 Hz, 1H), 12.15 (s, 1H). M− (ESI): 355.04; M+ (ESI): 356.99. HPLC (method A), Rt: 1.87 min (purity: 100%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=3[S:11][C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=1.Cl.[CH:19]1([NH:22][CH3:23])[CH2:21][CH2:20]1>CO>[CH:19]1([N:22]([C:2]2[C:3]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:4]=3[N:5]=[C:6]([CH2:8][O:9][CH3:10])[N:7]=2)[CH3:23])[CH2:21][CH2:20]1
Reactant: CNC1CC1
Reactant: COCc1nc(Cl)c2c3c(sc2n1)CCCC3
Agent: Cl
Solvent: CO
Product: COCc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirring suspension of compound 4-Chloro-2-methoxymethyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine (1.0 g, 0.0037 mol) and cyclopropyl methylamine hydrochloride (1.18 g, 0.111 mol) in methanol (100 ml) was added TEA (3.1 ml, 0.022 mol) at 0-5° C. Reaction mixture was then warmed to room temperature and stirred for about 20 h. After completion of the reaction (monitored by TLC) volatilities were removed under vacuum and solid residue obtained was diluted with ice-water solution (200 ml). Aqueous phase was extracted with DCM (2×250 ml). Combined organic layer was washed with brine solution, dried and concentrated on rotary evaporator to get crude material which was purified by prep HPLC to get the desired title compound cyclopropyl-(2-methoxymethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)-methyl-amine(N-cyclopropyl-2-(methoxymethyl)-N-methyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-amine) as a yellow solid. Yield: (600 mg, 54.5%); 1H), 2.90-2.87 (m, 2H), 2.83-2.80 (m, 2H), 1.88-1.82 (m, 2H), 1.72-1.68 (m, 2H), 0.76 1H NMR (400 MHz, DMSO) δ ppm=4.41 (s, 2H), 3.36 (s, 3H), 3.30 (s, 3H), 2.97-2.92 (m, −0.70 (m, 2H), 0.40-0.36 (m, 2H); LCMS: [M+H]=304.40; HPLC (purity): 99.61% at 236 nm, 99.45% at 220 nm, 99.32% at 254 nm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[N:32]=1.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([NH:20][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[N:32]=2)[CH:21]=[CH:22][CH:23]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(Nc2cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)n1
Yield: 81.8 %

Procedure:
A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (50 mg), tetrakistriphenylphosphine palladium (18 mg), potassium carbonate (24 mg), 2-chloro-6-methoxypyridine (25 mg) and toluene (3 ml) was heated under reflux under nitrogen atmosphere for 16 h and, thereafter, ethyl acetate and water were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=1:4) to give 54.5 mg of the titled compound (yield, 82%).
Reaction SMILES: [Br:1]Br.[C:3]([C:5]1[CH:9]=[C:8]([CH2:10][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:13])[CH3:12])[N:7]([CH2:22][CH2:23][O:24][CH3:25])[N:6]=1)#[N:4].C([O-])(=O)C.[K+].S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:9]1[C:5]([C:3]#[N:4])=[N:6][N:7]([CH2:22][CH2:23][O:24][CH3:25])[C:8]=1[CH2:10][C:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:13])[CH3:12]
Reactant: COCCn1nc(C#N)cc1CC(C)(C)NC(=O)OC(C)(C)C
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: COCCn1nc(C#N)c(Br)c1CC(C)(C)NC(=O)OC(C)(C)C
Reaction time: 9 h
Yield: 91.8 %

Procedure:
Bromine (19.5 g, 122 mmol) was added in a single portion to a solution of tert-butyl 2-[3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate (28.07 g, 87.1 mmol) and potassium acetate (12.8 g, 131 mmol) in acetic acid (174.2 mL). After 16 hours saturated aqueous sodium bisulfite was added until the reaction mixture was colorless. The acetic acid was removed under reduced pressure at about 30° C. The residue was made basic with 2 M sodium carbonate and then extracted with tert-butyl methyl ether (×3). The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. Analysis by HPLC indicated that the BOC group had been partially removed. The material was dissolved in dichloromethane (50 mL), combined with di-tert-butyl dicarbonate, and stirred for 9 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by IFC (65+M cartridge eluting with a gradient of 40 to 50% tert-butyl methyl ether in hexanes) to provide 32.1 g of tert-butyl 2-[4-bromo-3-cyano-1-(2-methoxyethyl)-1H-pyrazol-5-yl]-1,1-dimethylethylcarbamate as a colorless, viscous resin.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[NH2:26]>>[OH:15][C:12]1[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH2:2][NH:26][CH:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:16])[CH:8]=[CH:7]2
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: NC1Cc2ccccc2C1
Product: O=C(CNC1Cc2ccccc2C1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
5-(Chloroacetyl)-8-hydroxy-2(1H)-quinolinone (25 mg, 0.105 mmol) prepared from literature procedure (Yoshizaki, Shiro; Tanimura, Kaoru; Tamada, Shigeharu; Yabuuchi, Youichi; Nakagawa, Kazuyuki. J. Med. Chem. (1976), 19(9), 1138-42) is reacted neat with indan-2-ylamine (205 mg, 1.21 mmol) at 25° C. for 2 hours. The reaction mixture is purified by flash chromatography (silica, CH2Cl2/methanol 9:1). ES+ MS m/e 335 (MH+).
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][N:9]([CH3:15])[CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[CH2:16]([Sn:20]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21]I)[CH2:17][CH2:18][CH3:19]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:8][N:9]([CH3:15])[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:21][Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CN(C)CCCCO
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)COCCCCN(C)C
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
To a mixture of sodium hydride (72%, 232 mg, 7.0 mmol) and tetrahydrofuran (20 ml) was added 4-(dimethylamino)-1-butanol (0.82 g, 7.0 mmol) at 0° C. (external temperature), and the reaction mixture was stirred at 45° C. for 20 minutes. Then, the reaction mixture was cooled at 0° C. (external temperature). To the reaction mixture was added dropwise a mixture of tributyl-iodomethyl-tin (2.0 g, 4.6 mmol) and N,N-dimethylformamide (20 ml) at the same temperature. Then, the reaction mixture was stirred at 45° C. for 30 minutes. The reaction mixture was brought to room temperature, water and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethylacetate=20:1, NH silica gel) to obtain the title compound (1.4 g, 3.3 mmol, 70%).