Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[OH:13][C@H:14]([CH2:19][O:20][C@@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C:15](OC)=[O:16].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:13][C@@H:14]([CH2:19][O:20][C@H:21]([CH3:34])[CH2:22][O:23][Si:24]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[CH:25]([CH3:26])[CH3:27])[C:15]([NH:12][C:9]1[CH:8]=[N:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:16]
Reactant: Cc1cnc(N)cn1
Reactant: COC(=O)[C@H](O)CO[C@@H](C)CO[Si](C(C)C)(C(C)C)C(C)C
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cnc(NC(=O)[C@@H](O)CO[C@H](C)CO[Si](C(C)C)(C(C)C)C(C)C)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
Trimethylaluminium (2M solution in toluene) (72.5 mL, 145 mmol) was added to 5-methylpyrazin-2-amine (13.64 g, 125.0 mmol) in toluene (520 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (R)-methyl 2-hydroxy-3-((S)-1-(triisopropylsilyloxy)propan-2-yloxy)propanoate (Intermediate AU5) (33.5 g, 100.0 mmol) in toluene (130 mL) was added and the reaction was allowed to warm to room temperature and then stirred at 72° C. for 2.5 hours. The reaction mixture was allowed to cool then poured into a stirred mixture of ethyl acetate (500 mL) and aqueous solution of Rochelle salt (20% w/v, 500 mL). The mixture was stirred for 15 minutes then the organics separated and washed with water (500 mL) followed by brine (500 mL), then dried (MgSO4), filtered and concentrated. The residues were dissolved in iso-hexane (300 mL) and stood for 15 minutes at 20° C. before cooling to 5° C. over 30 minutes. The solid formed was isolated by filtration, washed with iso-hexane cooled to 5° C. (200 mL) and dried at 40° C. under high vacuum to afford the product (26.7 g, 64%). The filtrates were combined and concentrated to 100 mL total volume and the mixture stood for 16 hours. The solid formed was isolated by filtration, washed with iso-hexane cooled to 5° C. (100 mL), dried at 40° C. under high vacuum and combined with the initial batch to afford the product (30.1 g, 73%). 1H NMR (400 MHz, CDCl3) δ 1.04-1.17 (24H, m), 2.54 (3H, s), 3.62-3.67 (3H, m, 3.81-3.85 (1H, m), 4.05-4.09 (1H, m), 4.22 (1H, d), 4.34 (1H, q), 8.13 (1H, d), 9.12 (1H, s), 9.44 (1H, d); m/z (ES+) (M+H)+=412.34; HPLC tR=3.82 min.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.O>[C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1(C(=O)Nc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Methyl 1-(phenylcarbamoyl)cyclopropanecarboxylate (0.607 g, 2.77 mmol) was dissolved in a mixture of THF (3.5 mL) and water (3.50 mL), lithium hydroxide monohydrate (0.349 g, 8.31 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The THF was removed under reduced pressure and additional water (20 mL) was added. The solution was acidified to ˜pH 4 with 2 M HCl and the off white solid that precipitated was collected by suction filtration and washed with additional water to give 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (0.482 g, 85% yield). MS (ESI) m/z: 206.0 (M+H+)
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@H:34]2[C@@H:38]([O:39][CH2:40][CH2:41][F:42])[CH2:37][N:36]([C:43]([O:45][CH3:46])=[O:44])[CH2:35]2)=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@H:34]2[C@@H:38]([O:39][CH2:40][CH2:41][F:42])[CH2:37][N:36]([C:43]([O:45][CH3:46])=[O:44])[CH2:35]2)=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1cnc(CC)c(N[C@@H]2CN(C(=O)OC)C[C@@H]2OCCF)n1
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: CCc1nc(N[C@@H]2CN(C(=O)OC)C[C@@H]2OCCF)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting methyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-(2-fluoroethoxy)pyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, DMSO-d6) δ) 6.12, 4.49, 4.37, 4.21, 3.69-3.39, 2.71-2.55, 1.20-1.12; IR (liq.) 2973 (s), 2957, 2068 (b), 1996, 1705 (s), 1561 (s), 1541 (s), 1481 (s), 1454 (s), 1392 (s), 1191 (s), 1175, 1140 (s), 1114 (s), 1048, cm−1, HRMS (FAB) calcd for C16H24BrFN4O3+H 419.1094, found 419.1112. Anal. Calcd for C16H24BrFN4O3: C, 45.83; H, 5.77; N, 13.36. Found: C, 45.49; H, 5.81; N, 13.03.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38]>>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH:38][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: CN(C)CCN
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCN(C)C)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-dimethylaminoethylamine. ES-MS m/e (%): 457 (M+H+b , 100).
Reaction SMILES: CC(C)=O.[Cl:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:16])[C:13](Cl)=[O:14])[CH:9]=[CH:10][CH:11]=1.[C:17]([C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:16])[C:13](=[O:14])[O:28][C:23]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH:22]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)(C)c1cc(O)ccc1Cl
Reactant: CN(C(=O)Cl)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C(=O)Oc1ccc(Cl)c(C(C)(C)C)c1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To 30 ml of acetone were added 2.04 g of N-(3-chlorophenyl)-N-methylcarbamoyl chloride, 1.84 g of 3-tert-butyl-4-chlorophenol and 1.6 g of anhydrous potassium carbonate, and the mixture was refluxed with heating for 48 hours. The reaction mixture was cooled down to room temperature and thereafter was poured into cold water. The product was extracted with benzene. The benzene solution was washed with water and a saturated aqueous solution of sodium chloride in this order, and was dried over anhydrous magnesium sulfate. Thereafter, benzene was distilled off. The residue was purified through a column chromatography (employing silica gel as carrier and benzen as developing solvent), and further recrystallized from hexane to give 3.2 g of 3-tert-butyl-4-chlorophenyl N-(3-chlorophenyl)-N-methylcarbamate, having melting point of 65°-67° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14](C)=[N:15][N:16]=[C:9]1[CH:8]=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].I([O-])(=O)(=O)=[O:25].[Na+]>[Ru](=O)=O>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]([N:10]2[CH:14]=[N:15][N:16]=[C:9]2[CH3:8])=[C:6]([CH:5]=1)[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:25])([O-:3])=[O:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1nnc2cc(-c3ccccc3)c3cc([N+](=O)[O-])ccc3n12
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 3, 7-nitro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-nitro-2-(3-methyl- 4H-1,2,4-triazol-4-yl)-benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:13]([C:14]#[N:15])=[C:12]([N:16]=[CH:17][N:18](C)C)[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21](N)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:15][C:14]1[N:18]=[CH:17][N:16]=[C:12]2[NH:11][N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]=12)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN(C)C=Nc1[nH]nc(Nc2cccc(Cl)c2)c1C#N
Reactant: NCc1ccccc1
Product: Clc1cccc(Nc2n[nH]c3ncnc(NCc4ccccc4)c23)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Under a nitrogen atmosphere, a mixture of 1 g (3.46 mmol) of 3-(3-chloro-phenylamino)-4-cyano-5-(dimethylamino-methyleneamino)-pyrazole and 10 ml of benzylamine is stirred for 3 hours at 120° C. and then concentrated by evaporation under a HV. The crystalline residue is digested in 10 ml of acetonitrile, cooled to 0° C. and filtered and the filter residue is recrystallized from 35 ml of acetonitrile, yielding the title compound; m.p. 216-218° C.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[BH4-].[Na+].[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[S:22][C:23]4[CH2:29][C:28](=O)[CH2:27][CH:26]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[C:24]=4[N:25]=3)=[CH:16][C:15]=2[O:38][CH3:39])[CH:13]=1.Cl.[BH4-]>CO>[Cl:8][C:9]1[N:10]=[CH:11][N:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[S:22][C:23]4[CH2:29][CH:28]([NH2:5])[CH2:27][CH:26]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[C:24]=4[N:25]=3)=[CH:16][C:15]=2[O:38][CH3:39])[CH:13]=1
Reactant: COc1cc(Nc2nc3c(s2)CC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Product: COc1cc(Nc2nc3c(s2)CC(N)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 65 °C
Yield: 37.4 %

Procedure:
Ammonium acetate (123 mg, 1.599 mmol) and sodium borohydride (46.9 mg, 0.746 mmol) were added to a solution of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-4-(4-fluorophenyl)-4,5-dihydrobenzo[d]thiazol-6(7H)-one (50 mg, 0.107 mmol, from example 75) in MeOH (1.1 mL). The mixture was heated at 65° C. for 20 hours. Several drops of aqueous 1 M HCl were added to the reaction mixture to decompose the excess borohydride reagent. The solvent was removed in vacuo. The residue was made basic with 1N NaOH solution and extracted with dichloromethane. The crude product was purified using preparatory HPLC (Column: Phenomenex Luna C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 water/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 water/ACN, flow rate: 40 ml/min, 30-80% B, 18 min) to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(4-fluorophenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (21 mg, 0.040 mmol, 37.7% yield) as a white solid. LC-MS (M+H)+ 470.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.82 (d, J=2.52 Hz, 1 H) 7.63 (d, J=1.51 Hz, 1H) 7.33 (s, 1 H) 7.17-7.24 (m, 3 H) 7.13 (d, J=8.56 Hz, 1 H) 6.97-7.06 (m, 2 H) 6.64 (dd, J=8.56, 2.27 Hz, 1H) 4.00-4.23 (m, 3H) 3.31 (s, 3 H) 2.99-3.09 (m, 1 H) 2.70 (ddd, J=15.23, 9.69, 3.27 Hz, 1 H) 2.30-2.41 (m, 1 H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:25]=[C:24]([C:26]3[C:27]([O:41][C:42]4[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=4[C:49]#[N:50])=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]([C:36]([O:38][CH3:39])=[O:37])[C@@H:31]([CH3:40])[CH2:30][CH2:29]4)[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([O:41][C:27]2[C:26]([C:24]3[CH:23]=[N:22][N:21]([CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[CH:25]=3)=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][C@H:31]([CH3:40])[N:32]3[C:36]([O:38][CH3:39])=[O:37])=[C:43]([C:49]#[N:50])[CH:44]=1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.057 g, 0.094 mmol) in dichloromethane (2.0 mL) and the reaction mixture stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-methyl 5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.041 g, 86%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.09 (m, 4H), 1.49-1.79 (m, 4H), 1.80-2.07 (m, 4H), 2.52-2.63 (m, 2H), 2.99 (br d, J=12.31 Hz, 2H), 3.72 (s, 3H), 4.03-4.23 (m, 1H), 4.45-4.70 (m, 1H), 6.44 (br d, J=9.09 Hz, 1H), 7.47-7.64 (m, 3H), 7.67 (s, 1H), 7.95 (s, 1H), 8.10 (d, J=2.35 Hz, 1H). MS (ESI, pos. ion) m/z 506 [M+H]+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:13]=[C:12]2[C:7]=1[C@@H:8]1[CH:26]=[C:25]([CH3:27])[CH2:24][CH2:23][C@H:9]1[C:10]([CH3:22])([CH3:21])[O:11]2)CCC.[B-](F)(F)(F)[F:37].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC(C)=O.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[F:37][C:6]1[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:13]=[C:12]2[C:7]=1[C@@H:8]1[CH:26]=[C:25]([CH3:27])[CH2:24][CH2:23][C@H:9]1[C:10]([CH3:22])([CH3:21])[O:11]2
Reactant: F[B-](F)(F)F
Reactant: CCCCCc1cc2c(c([Sn](CCCC)(CCCC)CCCC)c1)[C@@H]1C=C(C)CC[C@H]1C(C)(C)O2
Agent: [Ag+]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(C)=O
Product: CCCCCc1cc(F)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Tributyl((6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-yl)stannane (S29) (100 mg, 0.17 mmol, 1 eq.) will be dissolved in acetone (3.5 ml), and AgOTf (87.4 mg, 0.34 mmol, 2 eq.) and Selectfluor (71 mg, 0.20 mmol, 1.2 eq.) will be added at room temperature. The mixture will be stirred for 20 min at room temperature and subsequently concentrated under reduced pressure. The concentrate will be subjected to column chromatography (EtOAc-Hex; 0:100 to 5:95) to give 19.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:13](=[S:41])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=S)c2-c2ccc(F)cc2)cc1
Yield: 88 %

Procedure:
A mixture of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared according to the method of Example 5, (109 mg, 0.25 mmol) and Lawesson's reagent (202 mg, 0.5 mmol) in 15 mL of toluene was stirred at reflux for 48 hours. The mixture was concentrated in vacuo and the residue was chromatographed (silica gel, ethyl acetate) to provide the title compound (yield: 100 mg, 88%). mp 88-90° C. 1H NMR (300 MHz, CDCl3) δ 3.04 (s, 3H), 6.05 (s, 2H), 6.96 (m, 2H), 7.08 (m, 2H), 7.26 (m, 2H), 7.37 (m, 3H), 7.61 (m, 2H), 7.84 (d, J=9 Hz, 2H), 8.13 (s, 1H). MS (DCI/NH3) m/z 451 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[F:10].[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1>>[F:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[CH2:2][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Fc1cccc(F)c1CBr
Product: Cc1cc(O)nc(SCc2c(F)cccc2F)n1
Yield: 79 %

Procedure:
As per procedure from Example 1, the title compound was prepared from 2-(bromomethyl)-1,3-difluorobenzene and 6-methyl-2-sulfanylpyrimidin-4-ol to provide the title compound as a white solid (1.02 g, 79% yield); NMR (400 MHz, DMSO-d6): δ 2.04 (s, 3H), 4.42 (s, 2H), 6.01 (bs, 1H), 7.12 (m, 2H), 7.38 (m, 1H), 12.29 (2 bs); M+268.8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(NC(C)C)(C)C>C(OCC)(=O)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:42]#[C:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccccc4)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A mixture of N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.17 g, 0.285 mmol), phenyl acetylene (0.07 ml, 0.63 mmol) and diisopropylamine (0.088 ml, 0.63 mmol) in ethyl acetate (4 ml) was cooled to −20 C under a nitrogen atmosphere. To this was added copper (I) iodide (0.016 g, 0.085 mmol) and bis(triphenylphospine)palladium (II) chloride (0.04 g, 0.057 mmol). The mixture was allowed to warm to ambient temperature and then stirred overnight. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-10% methanol in dichloromethane gave the product as a solid (0.108 g, 66%). NMR Spectrum: (DMSOd6 at 373k+d4 acetic acid) 2.10 (m, 2H), 2.76 (t, 4H), 2.83 (t, 2H), 3.69 (t, 4H), 3.97 (s, 3H), 4.24 (t, 2H), 6.12 (s, 2H), 7.15 (s, 1H), 7.30 (s(broad), 1H), 7.42 (m, 3H), 7.54 (m, 2H), 7.95 (s, 1H), 8.63 (s(broad), 1H). Mass Spectrum: M+H+ 573 and M+H− 571.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](OC)=[O:15])([O-])=O.Cl>C(OCC)(=O)C.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (1.3 g, 4.01 mmol) in ethyl acetate (18 mL) was added (pH3) HCl (5.2 mL) followed by 10% Pd/C (350 mg) in ethyl acetate (3 mL). The reaction mixture was stirred overnight under an atmosphere of H2. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude residue obtained was partitioned between dichloromethane (25 mL) and aqueous saturated NaHCO3 (15 mL). The organic phase was separated and the aqueous phase was extracted dichloromethane (2×25 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (50-100% ethyl acetate/hexanes) to give 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:15]=[C:16]([CH3:23])[CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:41](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][N:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:40][CH3:41])([C:36]([F:39])([F:37])[F:38])[C:32]([F:33])([F:34])[F:35])=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:15]=[C:16]([CH3:23])[CH:17]=[C:18]3[C:22]=2[NH:21][CH:20]=[CH:19]3)=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(C(=O)N(CCc2ccc(Cl)c(Cl)c2)Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)c2[nH]ccc2c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(c1ccc(CN(CCc2ccc(Cl)c(Cl)c2)C(=O)c2cc(C)cc3cc[nH]c23)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
20 mg of 5-methyl-1H-indole-7-carboxylic acid [2-(3,4-dichloro-phenyl)-ethyl]-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-benzyl]-amide (0.03 mmol) were dissolved in 5 ml DMF and potassium carbonate (9 mg, 0.07 mmol) and methyl iodide (3 μl, 0.05 mmol) were added. The reaction mixture was stirred over night at rt, then saturated ammonium chloride solution was added and the mixture was extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried with magnesium sulfate, filtrated and concentrated. The remaining residue was purified by silica gel filtration (hexane/EtOAc 1:1). This gave 20 mg (98%) of the title compound as a white foam. MS (ISP) 617.2 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)C1C=CC=CC=1.C(N1CCCOCC1)C1C=CC=CC=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>[C].[Pd].CO>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[OH:15][CH2:14][C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: c1ccc(CN2CCCOCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: OC[C@H]1CNCCO1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
In the same manner as in Example 3, a mixture containing N-benzyl-2-hydroxymethylmorpholine, N-benzyl-1,4-oxazepane and other byproducts (121.1 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=75.1:24.9). To this mixture were added methanol (200 ml), trifluoroacetic acid (61.8 g, 0.540 mol), and palladium carbon (11.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, and methanol was evaporated under reduced pressure. The residue was subjected twice to azeotropic distillation with dehydrating with 2-propanol (100 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (450 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (100 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (53.7 g) (yield from (S)-epichlorohydrin: 43.0%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee.