Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([N+:24]([O-])=O)=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(OCCCC)CCC.C(O)(=O)C>[Fe].O>[NH2:24][C:19]1[CH:20]=[C:21]([O:22][CH3:23])[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2
Reactant: CCCCCCCCCCOc1c(OC)cc([N+](=O)[O-])c2ncccc12
Agent: [Fe]
Solvent: CCCCOCCCC
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCOc1c(OC)cc(N)c2ncccc12
Yield: 83.8 %

Procedure:
A stirred mixture of 4.7 g (0.013 mole) of 5-decoxy-6-methoxy-8-nitroquinoline, 12 g of degreased 40 mesh iron filings, 6 ml of butyl ether, 6 ml of acetic acid and 30 ml of water was heated at 100° for 2 hr, cooled and filtered. The solid was washed with water, dried and extracted with diethyl ether. Evaporation of the diethyl ether, solution of the residue in petroleum ether (20°-40°) and cooling in Dry-Ice acetone gave 3.6 g of pale green solid. Two crystallizations from petroleum ether (20°-40°) (carbon) provided 2.3 g (54%) of amino compound as yellow-green solid, mp 65°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15]I.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:12][CH2:13][CH2:14][CH2:15][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: O=C1COc2ccccc2N1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 40 h
Yield: 87.3 %

Procedure:
A reaction flask was charged with 4H-benzo[1.4]oxazin-3-one (1.48 g, 10 mmol), 1-chloro-3-iodopropane (2.04 g, 10 mmol), and Cs2CO3 (4.88 g, 15 mmol) in MeCN (10 mL) and stirred at rt for 40 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (1.97 g, 88%). 1H NMR (CDCl3) d 7.06-7.02 (m, 2H), 7.01-6.99 (m, 2H), 4.58 (s, 2H), 4.12-4.07 (m, 2H), 3.64-3.60 (m, 2H), 2.19-2.12 (m, 2); 13C NMR (CDCl3) d 164.7, 145.6, 128.6, 124.2, 123.2, 117.5, 114.9, 67.8, 42.6, 39.1, 30.3.
Reaction SMILES: [Si](O[N:9]=[C:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[CH:15][CH:16]=2)[C:11]1=[O:20])(C(C)(C)C)(C)C.CO.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>O1CCCC1.ClCCl.O>[OH:20][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=2)[CH2:18][CH:10]1[NH:9][C:31](=[O:32])[O:33][CH2:34][CH3:35]
Reactant: Cc1ccc2c(c1)C(=O)C(=NO[Si](C)(C)C(C)(C)C)C2
Reactant: CCOC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)NC1Cc2ccc(C)cc2C1O
Temperature: 63 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
The compound (6.00 g, 20.7 mmol) obtained in step B was dissolved in tetrahydrofuran (100 ml), and the mixture was stirred with heating at 63° C. At the same temperature, 1 mol/L borane-tetrahydrofuran complex/tetrahydrofuran solution (41.4 ml, 41.4 mmol) was slowly added dropwise. The mixture was stirred at the same temperature for 2.5 hr, cooled to room temperature and methanol was slowly added dropwise with stirring. The reaction solution was concentrated under reduced pressure, methanol and toluene were added again, and the solution was concentrated under reduced pressure. This was repeated 4 times, and the obtained colorless solid and triethylamine (3.5 ml, 24.8 mmol) were dissolved in dichloromethane (50 ml) and the mixture was stirred under ice-cooling. Then, ethyl chloroformate (2.2 ml, 22.8 mmol) was added, and the mixture was stood at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography (methanol-chloroform) to give the title compound (3.30 g, yield 67%) as a colorless oil.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH3:22])=[C:14]([NH2:23])[C:13]=2[C:24]2[C:25](F)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH3:32][C:33]([OH:35])=[O:34]>>[C:33]([OH:35])(=[O:34])[CH3:32].[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([CH3:22])=[C:14]3[C:13]=2[C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[N:26][C:25]=2[NH:23]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c(N)c2-c2cc(C)cnc2F)c1
Solvent: CC(=O)O
Product: CCS(=O)(=O)c1cccc(-c2cc(C(F)(F)F)c(C)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
3′-(ethylsulfonyl)-2-(2-fluoro-5-methylpyridin-3-yl)-4-methyl-5-(trifluoromethyl)biphenyl-3-amine (4.9 g, 10.8 mmol) was dissolved in HOAc (35 mL) and heated at reflux for 3 h. The reaction mixture was cooled to room temperature affording a crystalline product. The resulting suspension was filtered, rinsed with HOAc (3×5 mL) followed by H2O (3×10 mL) and the solids dried in vacuo to give 3.73 g (70%) of the title compound as a white solid. NMR analysis confirmed that the product was isolated as the mono-acetate salt. 1H NMR (400 MHz, DMSO-d6): δ 12.35 (s, 1H), 12.0 (s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 8.04-8.09 (m, 2H), 7.90 (t, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 3.43 (q, 2H), 2.76 (s, 3H), 2.28 (s, 3H), 1.91 (s, 3H), 1.18 (t, 3H). MS (ES) [m+H] calc'd for C22H19F3N2O2S, 433; found 433.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1.[OH:26][C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:30]1[CH2:31][CH2:32][C:27]([OH:26])([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:28][CH2:29]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Product: Cc1nc2ccc(N3CCC(O)(c4ccccc4)CC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 29 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 4-hydroxy-4-phenylpiperidine according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 29%; MS: m/z=491 (M+H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][CH:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][S:6]1(=[O:21])=[O:20])=[N+]=[N-].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH:8]2[CH2:7][S:6](=[O:21])(=[O:20])[CH:5]([CH2:4][NH2:1])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CSC2CC(CN=[N+]=[N-])S(=O)(=O)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CSC2CC(CN)S(=O)(=O)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A 0° C. solution, under argon, of 1.4 g of product from Example 179 in 14 ml of dry methylene chloride is treated with 1.19 ml of triethylamine. Hydrogen sulfide gas is slowly bubbled through the cold solution for 20 minutes (the excess gas is trapped in a flask containing an aqueous solutin of 5.25% sodium hypochlorite). The mixture is stirred at 0° C. for 2 hours, the flask flushed for 20 minutes with argon and the reaction is concentrated in vacuo. The residue is purified by chromatography (silica gel: 10-100% ethyl acetate/hexane, 5% methyl alcohol/ethyl acetate) to give 0.757 g of the desired product (mixture of isomers).
Reaction SMILES: [I:1][C:2]1[C:19](O)=[N:18][C:5]2[CH2:6][CH2:7][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH:10]([CH3:11])[C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:23]>CN(C=O)C>[Cl:23][C:19]1[C:2]([I:1])=[CH:3][C:4]2[CH:10]([CH3:11])[CH2:9][N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:7][CH2:6][C:5]=2[N:18]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2nc(O)c(I)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CC1CN(C(=O)C(F)(F)F)CCc2nc(Cl)c(I)cc21
Temperature: 100 °C
Yield: 40 %

Procedure:
A mixture of 3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepin-2-ol (137 mg, 342 μmol), DMF (100 μl) and POCl3 (5 ml) was heated at 100° C. for 16 h. The reaction mixture was concentrated in vacuo and purified by column chromatography to furnish 57.0 mg (40%) of 2-chloro-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. MS (ESI) m/z 419.1/421.1. A mixture of 2-chloro-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (58.0 mg, 139 μmol), K2CO3 (50 mg) and MeOH (10 ml) was heated for 1 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography furnishing 37.7 mg (84%) of 2-chloro-3-iodo-5-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 3.13 (m, 2H), 3.07-2.92 (m, 4H), 2.75 (dd, 1H), 1.33 (d, 3H) ppm.
Reaction SMILES: C(C1OC2C=CC(Cl)=CC=2C=1)(=O)C1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26](/[C:28](/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=2[CH:41]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26](/[C:28](/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=2[CH:41]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1cc2cc(Cl)ccc2o1
Agent: O=C(c1ccccc1)c1cc2cc(Cl)ccc2o1
Product: CCOC(=O)/C=C(\c1ccccc1)c1cc2cc(Cl)ccc2o1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 2-benzoyl-5-chlorobenzofuran, a mixture of (Z)-ethyl 3-(5-chloro-2-benzofuranyl)-3-phenylacrylate and (E)-ethyl 3-(5-chloro-2-benzofuranyl)-3-phenylacrylate was obtained as yellowish oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>CO>[S:6]1[C:2]([NH:13][CH2:10][CH2:11][CH3:12])=[N:3][N:4]2[CH:9]=[CH:8][N:7]=[C:5]12
Reactant: CCCN
Reactant: Brc1nn2ccnc2s1
Solvent: CO
Product: CCCNc1nn2ccnc2s1
Temperature: 175 °C

Procedure:
1.5 g of 2-bromo-imidazo[2,1-b][1,3,4]thiadiazole were dissolved in 10 ml methanol and 10 ml of propylamine were added to the solution. The resulting mixture was heated in a microwave oven at 175° C. for 15 min. The resulting suspension was evaporated and dissolved in ethylacetate. It was washed with water, dried with sodium sulphate and evaporated. Silica-gel chromatography with petroleum ether-ethylacetate gave 519 mg of the desired product as solid material.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.C(NC(C)C)(C)C.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[N+:3]([CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[C-:1]
Reactant: O=CNCCCNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC(C)NC(C)C
Product: [C-]#[N+]CCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
To a solution of benzyl [3-(formylamino)propyl]-carbamate (15.8 g, 67.0 mmol) in 300 mL of dry CH2Cl2 was added diisopropylamine (29.6 mL, 211 mmol). The solution was cooled down to 0° C. using an ice bath. Then, POCl3 (7.36 mL, 80.0 mmol) was slowly added dropwise. After warming to room temperature, the solution was stirred for a further 3 h. Addition of 20 g of Na2CO3, dissolved in 100 mL of distilled H2O, was followed by further stirring at RT for 30 min. The reaction mixture was subsequently diluted with 100 mL of CH2Cl2 and also 100 mL of distilled H2O and the aqueous phase was extracted 3× with 150 mL of CH2Cl2 each time. The combined organic phases were dried over Na2SO4 and concentrated in a rotary evaporator. Purification by column chromatography (MeOH/CH2Cl2, 1/9, v/v) gave a dark brown liquid (13.0 g, 89%).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[N:9][CH:10]=1>O1CCCC1>[Br:4][C:5]1[CH:6]=[C:7]([C:11]([OH:13])([CH3:1])[CH3:12])[CH:8]=[N:9][CH:10]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cncc(Br)c1
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Methyl magnesium bromide (5.3 mL, 0.075 mol) was added to a stirred solution of 1-(5-bromopyridin-3-yl)ethanone (1.0 g, 0.05 mol) in tetrahydrofuran (20.0 mL), cooled to 0° C. and the resulting mixture was allowed to warm to room temperature and stirred for 1.5 h. The reaction mixture was quenched with 1N hydrochloric acid (20 mL) and extracted with ethyl acetate (2×75 mL). The combined organic layers were dried over sodium sulphate and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain 2-(5-bromopyridin-3-yl)propan-2-ol. MS (M+1): 217.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:26]([CH:23]4[CH2:25][CH2:24]4)=[O:27])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)C4CC4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 62.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.00 g, 3.10 mmol) and cyclopropanecarbonyl chloride (0.32 g, 3.10 mmol) in THF (35 mL), was added triethylamine (0.88 mL, 6.20 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 6 h then cooled to rt. The mixture was filtered and the filtrate diluted with EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (100 mL), water (2×75 mL), dried (MgSO4) and concentrated in vacuo to give cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.69 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 2.96 min (98.96%); mp: 163-165° C.; 1H NMR (DMSO-d6) δ 0.62-0.78 (m, 4H), 1.63 (m, 1H), 1.95-2.17 (m, 1H), 2.53-2.67 (m, 2H), 2.79-3.00 (m, 1H), 4.46 (d, J=6.0 Hz, 2H), 5.15 (dd, J=5.4, 12.9 Hz, 1H), 7.67-7.79 (m, 2H), 7.89 (d, J=7.6 Hz, 1H), 8.77 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 6.44, 13.57, 21.99, 30.93, 42.05, 48.99, 121.83, 123.54, 129.74, 131.60, 133.35, 147.77, 166.99, 167.13, 169.82, 172.73, 172.94; Anal Calcd for C18H17N3O5+0.2H2O: C, 60.23; H, 4.89; N, 11.71. Found: C, 60.16; H, 4.54; N, 11.70.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[Cl:10][C:11]1[O:15][C:14]([CH:16]2[C:21]3=[C:22]4[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]4=[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:20]3[CH2:19][CH:18]([CH2:39]O)[S:17]2)=[CH:13][CH:12]=1.[N:41]1[C:46](C)=CC=C[C:42]=1C.CNC>C(Cl)Cl>[Cl:10][C:11]1[O:15][C:14]([C@@H:16]2[C:21]3=[C:22]4[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]4=[C:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:20]3[CH2:19][C@H:18]([CH2:39][N:41]([CH3:46])[CH3:42])[S:17]2)=[CH:13][CH:12]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)SC(CO)C3
Reactant: Cc1cccc(C)n1
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: ClCCl
Product: CN(C)C[C@H]1Cn2c(-c3ccccc3)c3c(=O)n(C)c(=O)n(C)c3c2[C@@H](c2ccc(Cl)o2)S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanesulfonic anhydride (60.9 mg, 0.35 mmol) was added to a solution of 10-(5-chlorofuran-2-yl)-8-(hydroxymethyl)-1,3-dimethyl-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione (Example 12.0) (160 mg, 0.35 mmol) and 2,6-lutidine (0.041 ml, 0.35 mmol) in DCM (16 ml) at 0°. The mixture was stirred at room temperature for 2 hours. The mixture was evaporated under vacuum and the residue redissolved in THF (6 ml). Dimethylamine solution (2M in THF, 6 ml, 12.0 mmol) was added and mixture stirred at room temperature for 1 h, at 35° C. for 16 hours, at 55° C. for 6 hours, again at room temperature for 3 days, then at 55° C. for 4 hours, and finally heated under microwave irradiation at 80° C. for 20 mins. The mixture was evaporated under vacuum. The residue was redissolved in DCM and methanol and loaded onto an Isolute™SCX-2 cartridge. The column was first rinsed with methanol/DCM (1:1, 50 ml) then eluted with 3.5 M NH3/methanol (50 ml). The basic eluent was evaporated under vacuum to afford the title compounds as a mixture of diastereomers
Reaction SMILES: C(OC(N[C@@H](C(C)C)C(O)=O)=O)(C)(C)C.C(OC(NC(C(C)(C)C)C(O)=O)=O)(C)(C)C.[NH2:32][C@@H:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1.C(OC(=O)NC(C(=O)NC1C2C(=CC=CC=2)CC1O)C(C)(C)C)(C)(C)C.ClNC(=O)[O-].C([O:75][C:76]([C:78]1([NH:83][C:84]([CH:86]2[CH2:90][CH:89]([O:91][C:92]3[C:101]4[C:96](=[CH:97][C:98]([O:102][CH3:103])=[CH:99][CH:100]=4)[N:95]=[C:94]([C:104]4[CH:109]=[CH:108][CH:107]=[CH:106][CH:105]=4)[CH:93]=3)[CH2:88][N:87]2[C:110](=[O:130])[NH:111][CH:112]([C:117](=[O:129])NC2C3C(=CC=CC=3)CC2O)[C:113](C)([CH3:115])[CH3:114])=[O:85])[CH2:80][CH:79]1[CH:81]=[CH2:82])=[O:77])C>>[C@@H:33]1([NH:32][C:117]([C@@H:112]([NH:111][C:110]([N:87]2[CH2:88][C@H:89]([O:91][C:92]3[C:101]4[C:96](=[CH:97][C:98]([O:102][CH3:103])=[CH:99][CH:100]=4)[N:95]=[C:94]([C:104]4[CH:105]=[CH:106][CH:107]=[CH:108][CH:109]=4)[CH:93]=3)[CH2:90][C@H:86]2[C:84]([NH:83][C@:78]2([C:76]([OH:77])=[O:75])[CH2:80][C@H:79]2[CH:81]=[CH2:82])=[O:85])=[O:130])[CH:113]([CH3:115])[CH3:114])=[O:129])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34]1
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C)C(=O)OCC
Reactant: N[C@H]1CCc2ccccc21
Agent: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Agent: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)N[C@H](C(=O)N[C@H]1CCc2ccccc21)C(C)C)C(=O)O
Yield: 49 %

Procedure:
(2S)-tert-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 followed by reaction with (1S)-1-aminoindane as described for the preparation of 17 and removal of the Boc group as described for 18. The afforded compound was then reacted with the chlorocarbamate achieved from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (22 mg, 49% yield), Purity by HPLC>90% M+H+732.2.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[NH:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=2)[CH2:2]1.[CH3:16]COCC>CO.C(N(CC)CC)C>[CH3:16][N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[NH:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH:8]=2)[CH2:2]1
Reactant: c1cnc2[nH]c(CC3CCNC3)cc2c1
Reactant: CCOCC
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCC(Cc2cc3cccnc3[nH]2)C1

Procedure:
Compound 66 (0.3 g, 1.49 mmol) was converted to compound 67, using the methodology described for compound 9. Yield 0.362 g (80.7%). (TLC ether Rf 0.11), which was used as such to generate the title compound (68) using the methodology as described for compound 28.(Yield 0.17 g, 65%), mp 96-97° C. 1H-NMR (400 MHz, CDCl3): δ N1—H invisible, 8.16 (dd, J=5 Hz, 2 Hz, 1H), 7.77 (dd, J=8 Hz, 2 Hz, 1H), 6.98 (dd, J=8 Hz, 5 Hz, 1H), 6.16 (bs, 1H), 2.92-2.84 (m, 2H), 2.76-2.64 (m, 2H), 2.62-2.50 (m, 2H), 2.34 (s, 3H), 2.40-2.31 (m, 1H), 2.11-2.01 (m, 1H), 1.63-1.53 (m, 1H). (TLC MeOH/triethylamine (97/3) Rf 0.2).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.C[Si](C)(C)[O:12][C:13]1[CH:14]=[CH:15][C:16](Cl)=[N:17][CH:18]=1.C(=O)([O-])O.[Na+]>C(OCC)C.CC(P(C1C=CC=CC=1)C1C=CC=CC=1)C.C1C=CC(PC2C=CC=CC=2)=CC=1.[Cl-].[Ni].O1CCCC1>[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:3]2[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=2)=[N:17][CH:18]=1
Reactant: Brc1ccc(Br)cc1
Reactant: C[Si](C)(C)Oc1ccc(Cl)nc1
Agent: [Ni]
Agent: CC(C)P(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1ccc(-c2ccc(Br)cc2)nc1
Reaction time: 3 h
Yield: 67.2 %

Procedure:
A Grignard reagent solution prepared from 0.8 g of magnesium, 8.0 g of 1,4-dibromobenzene and 50 ml of tetrahydrofuran was added dropwise at 0°-5° C. within 30 minutes to a mixture of 6.6 g of 5-trimethylsilyloxy-2-chloropyridine, 75 ml of tetrahydrofuran and 0.4 g of 1,3-bis(diphenylphosphino)-propanenickel(II) chloride. The reaction mixture was stirred for 3 hours, left to stand overnight, then adjusted to pH 8 with aqueous sodium hydrogen carbonate solution and diluted with diethyl ether. The organic phase was washed neutral with water, dried over sodium sulfate and concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 4:1) yielded 5.5 g of 5-hydroxy-2-(4-bromophenyl)-pyridine.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:38]=[CH:37][C:23]([O:24][C:25]2[C:34]3[NH:33][C:32](=[O:35])[C:31]([CH3:36])=[N:30][C:29]=3[N:28]=[CH:27][CH:26]=2)=[CH:22][C:21]=1[F:39]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:19][C:20]2[CH:38]=[CH:37][C:23]([O:24][C:25]3[C:34]4[NH:33][C:32](=[O:35])[C:31]([CH3:36])=[N:30][C:29]=4[N:28]=[CH:27][CH:26]=3)=[CH:22][C:21]=2[F:39])=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2nccc(Oc3ccc(N)c(F)c3)c2[nH]c1=O
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: Cc1nc2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c(F)c3)c2[nH]c1=O

Procedure:
Method F3 was used with 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole and 8-(4-Amino-3-fluorophenoxy)-3-methylpyrido[2,3-b]pyrazin-2(1H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:37]1[CH:38]=[C:33]([CH3:32])[CH:34]=[CH:35][CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: Cc1cccc(B(O)O)c1
Product: COC(=O)c1c(-c2cccc(C)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 3-methylphenylboronic acid. A colorless powder (63 mg).