Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10])=[CH:6][C:5]([NH:14][C:15]([N:17]2[CH2:21][C@H:20]([OH:22])[CH2:19][C@@H:18]2[C:23](O)=[O:24])=[O:16])=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)O>C(C(C)=O)C(C)C>[Cl:13][CH2:12][S:9]([NH:8][C:7]1[CH:6]=[C:5]([N:14]2[C:23](=[O:24])[C@H:18]3[CH2:19][C@@H:20]([OH:22])[CH2:21][N:17]3[C:15]2=[O:16])[C:4]([F:26])=[CH:3][C:2]=1[Cl:1])(=[O:11])=[O:10]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Agent: O=S(=O)(O)O
Solvent: CC(=O)CC(C)C
Product: O=C1[C@H]2C[C@@H](O)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.9 %

Procedure:
295.5 g (0.25 mol) of (2R-cis)-1-[[[4-chloro-5-[[(chloromethyl)sulfonyl]amino]-2-fluorophenyl]amino]carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid was suspended in 150 g of methyl isobutyl ketone at room temperature. 12.75 g (0.125 mol) of concentrated sulfuric acid was added and the clear solution was heated to reflux. At 90° C. a precipitate appeared. After an additional 20 minutes of stirring at reflux the suspension was cooled to 0° C. and allowed to stir for 1 hour at this temperature. After filtration and drying at 60° C., 91.65 g (86.6%) of the title compound was obtained as beige crystals melting at 198-200° C. (purity: 97%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([O:15]N2C3C=CC=CC=3N=N2)=O)[N:10]=[CH:9]1.[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>CN(C=O)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([N:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[CH3:36])=[O:15])[N:10]=[CH:9]1
Reactant: CNCc1ccccn1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)On4nnc5ccccc54)c3)c(F)c2)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)N(C)Cc4ccccn4)c3)c(F)c2)C(=O)O1
Yield: 22 %

Procedure:
N-[(5S)-3-(3-fluoro-4-(4-(1-benzotriazolyloxy)carbonylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (prepared as detailed for Exarnples 49-80; 243 mg, 0.5 mM) dissolved in DMF (4 ml) was treated with 2-(N-methylaminomethyl)pyridine (68 mg, 0.55mM). The mixture was stirred under nitrogen, and heated to 55° for 18 hours. After cooling, the mixture was diluted with saturated sodium bicarbonate solution (20 ml), extracted with ethyl acetate (2×10 ml), the extract washed with water and dried over magnesium sulfate. After evaporation the residue was dissolved in dichloromethane and the solution chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 20% methanol in dichloromethane. Relevant fractions were combined and evaporated to give title product (52 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
4-(4-Nitro-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.4 mmol) was suspended in a 5:1 mixture of ethanol and water (3 ml). To this solution was added iron powder (0.4 g, 0.98 mmol) followed by saturated ammonium chloride solution (1 ml) and the mixture was stirred at room temperature for 18 hours. After this time, the reaction mixture was filtered through a pad of celite, the celite was washed with ethanol (10 ml) and ethyl acetate (50 ml) and the solution was concentrated under vacuum. The resulting residue was partitioned between DCM (50 ml) and water (20 ml), the organic layer was separated, dried with MgSO4, filtered and concentrated to afford the title compound (0.114 g, 83% yield) as a yellow solid. Tr=1.37 min, m/z (ES+) (M+Na)+ 363.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.[CH3:12]I>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:12])[S:8][C:7]=2[CH:11]=1
Reactant: COc1ccc2ccsc2c1
Reactant: CI
Product: COc1ccc2cc(C)sc2c1
Yield: 64.5 %

Procedure:
The same operations as in Preparation example 1 were carried out using 180 mg of 6-methoxybenzo[b]thiophene, and 450 mg of methyl iodide in place of cyclohexanone, and then purification was carried out by TLC (developing solvent, chloroform:n-hexane=1:19) to obtain 126 mg of 6-methoxy-2-methylbenzo[b]thiophene.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C=O)C>[N+:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[NH:22][C:21]1[CH:23]=[CH:24][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Nc2ccc(OC(F)(F)F)cc2)c([N+](=O)[O-])c1

Procedure:
A stirred solution of methyl 4-fluoro-3-nitrobenzoate (853 mg, 4.28 mmol), 4-trifluoromethoxyaniline (759 mg, 4.28 mmol) and triethylamine (1.79 mL, 12.9 mmol) in DMF (5.00 mL) was heated to 70° C. for 24 h. The reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-10% methanol/DCM as eluent) afforded the title compound i-3a. m/z (ES) 357 (MH)+. 1H NMR (500 MHz, CDCl3): δ 9.77 (s, 1H), 8.96 (s, 1H), 8.03 (d, 1H, J=8.5 Hz), 7.34 (m, 4H), 7.16 (d, 1H, J=8.5 Hz), 3.95 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH3:36][O:37][P:38]([CH2:58][NH2:59])([CH2:40][CH:41]([C:46](=[O:57])[NH:47][C@H:48]([C:53](=[O:56])[NH:54][CH3:55])[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39]>O1CCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:17](=[O:19])[NH:59][CH2:58][P:38]([O:37][CH3:36])([CH2:40][CH:41]([C:46](=[O:57])[NH:47][C@H:48]([C:53](=[O:56])[NH:54][CH3:55])[CH2:49][CH:50]([CH3:52])[CH3:51])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:39])[CH2:13][CH:14]([CH3:15])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)OC
Reaction time: 3.5 h
Yield: 64 %

Procedure:
A solution of 0.53 g of N-[(benzyloxy)carbonyl]-L-leucine in 10 ml of dry tetrahydrofuran was cooled to -30° C. and there was then added 0.23 g of N-ethylmorpholine followed by 0.27 g of isobutyl chloroformate. After stirring at -30° C. for 5 minutes a solution of 0.6 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester, prepared as described in Example 2(A)(i), and 0.23 g of N-ethylmorpholine were added. The mixture was left to come to room temperature and was stirred at this temperature for 3.5 hours. The mixture was then diluted with 50 ml of dichloromethane, washed with 20 ml of 10% sulfuric acid, 20 ml of sodium chloride solution and 20 ml of saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and evaporated to give a colorless gum. This gum was purified by flash chromatography on silica gel using 10% methanol in ethyl acetate for the elution to give 0.645 g of benzyl[(S)-1-[[[methoxy[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinyl]methyl]carbamoyl]-3-methylbutyl]carbamate in the form of a white foam.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[CH2:13]([N:15]1[C:20]2[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=2[C:18](=O)[O:17]C1=O)[CH3:14]>CN(C=O)C>[NH2:4][C:3]1[N:15]([CH2:13][CH3:14])[C:20]2[C:19]([C:18](=[O:17])[C:2]=1[C:1]#[N:5])=[CH:24][CH:23]=[C:22]([I:25])[CH:21]=2
Reactant: N#CCC#N
Reactant: CCn1c(=O)oc(=O)c2ccc(I)cc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C#N)c(=O)c2ccc(I)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
0.32 g (6.31 mmol) of malononitrile and 1.45 g (14.35 mmol) triethylamine were added to 2 g (6.31 mmol) of 1-ethyl-7-iodo-1H-benzo[d][1,3]oxazine-2,4-dione dissolved in 25 mL of DMF. The solution was stirred for 2 hours at 120° C. and after addition of 0.73 g (7.17 mmol) of triethylamine, for another 1 hour at 110° C. The DMF was then evaporated under reduced pressure and the residue taken over with a mixture of water and dichloromethane. Filtration of this mixture gave a first fraction of the expected compound: 0.55 g (1.62 mmol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])=[N:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][C:4]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])=[N:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(COc1ccc(C#N)cc1)n2C)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccncn1
Yield: 14 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[(4-cyanophenyl)oxymethyl]-benzimidazol-5-yl-carboxylic acid-N-(4-pyrimidyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 14% of theory, C26H27N7O4 (501.6) Mass spectrum: (M+H)+ =502
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([P:19]([CH2:24][CH2:25][CH3:26])([CH2:21][CH2:22][CH3:23])=[O:20])[CH:14]=2)[N:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]2)=[C:32]2[C:36]=1[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]2>>[CH2:21]([P:19]([C:15]1[CH:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C@H:39]4[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41][CH2:40]4)=[C:32]4[C:36]=3[C:35](=[O:37])[N:34]([CH3:38])[CH2:33]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)[CH:18]=[CH:17][CH:16]=1)([CH2:24][CH2:25][CH3:26])=[O:20])[CH2:22][CH3:23]
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Reactant: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c1
Product: CCCP(=O)(CCC)c1cccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c1

Procedure:
The title product was prepared according to the procedure for Example 102 using 4-chloro-N-[3-(dipropylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (Compound 1688) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (t, J=7.33 Hz, 6H), 1.24-1.40 (m, 4H), 1.42-1.58 (m, 4H), 1.79 (d, J=12.88 Hz, 2H), 1.82-1.89 (m, 2H), 1.89-1.98 (m, 4H), 3.08 (s, 3H), 3.42-3.54 (m, 1H), 4.54 (s, 2H), 4.64 (br. s., 1H), 7.26 (br. s., 1H), 7.63-7.72 (m, 2H), 7.79 (d, J=6.57 Hz, 2H), 8.52 (s, 1H), 8.62 (br. s., 1H), 10.14 (s, 1H), 10.59 (br. s., 1H). MS (ES+): m/z=630.27 [MH+]. HPLC: tR=3.17 min (ZQ3, polar—5 min).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:18][CH2:12][C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(OCc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-benzyloxybenzyl alcohol (2 g, 9.3 mmol) and carbon tetrabromide (4 g, 12.1 mmol) in CH2Cl2 (70 mL), cooled to 0° C., was added a solution of triphenylphosphine (2.9 g, 11.2 mmol) in CH2Cl2 (20 mL). The reaction was stirred at rt for 3 h and concentrated. Purification by flash chromatography (silica gel, 0-8% EtOAc/hexanes) gave 1-((3-(bromomethyl)phenoxy)methyl)benzene. 1H NMR (400 MHz, CDCl3) δ 7.39 (m, 5H), 7.25 (m, 1H), 7.00 (m, 2H), 6.92 (m, 1H), 5.06 (s, 2H), 4.46 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[CH:23])=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[C:25]1[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[N:12]3[N:19]=[CH:20][C:21]([C:22]#[C:23][C:25]4[S:29][C:28]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:27][CH:26]=4)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)s1
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)s1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.9) (89 mg, 0.25 mmol) and 5-bromo-thiophene-2-sulfonic acid amide (61 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (42 mg, 32%). MS (ISP) 517.0 [(M+H)+]; mp 231–232° C.
Reaction SMILES: [CH2:1]([CH:8]1[C:14](=[O:15])[CH2:13][CH:12]2[CH2:16][CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CC([O-])(C)C.[K+].C1COCC1.[N:28](OCCC(C)C)=[O:29].Cl>C1COCC1>[CH2:1]([CH:8]1[C:14](=[O:15])[C:13](=[N:28][OH:29])[CH:12]2[CH2:16][CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CC2CCC(C2)C1Cc1ccccn1
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1C(=NO)C2CCC(C2)C1Cc1ccccn1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
To a solution of 2-aza-2-benzyl-3-oxobicyclo[3.2.1]octane in THF was added 2.5 eq. of 1M t-BuOK/THF (Aldrich) and the resulting mixture was stirred for 30 minutes. Isoamyl nitrite (1.5 eq.) was then added dropwise and the reaction mixture was stirred overnight. To the reaction mixture was added 3N HCl and this mixture was extracted with ethyl acetate and the organic extracts washed with water, dried, and concentrated under reduced pressure. The residue was triturated with ether/hexanes, the solvents decanted and the residue dried under reduced pressure to afford 2-aza-2-benzyl-4-oximino-3-oxobicyclo[3.2.1]octane as a tan liquid (41% yield). This procedure is further described in Y. Kim, Tetrahedron Lett. 30(21), 2833-2636 (1989).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:22]2[CH:21]([CH2:20][CH2:19][CH2:18][C:17]2=[O:23])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCC2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzyl-methoxymethyl-trimethylsilanylmethyl-amine (29.6 g, 0.12 mol) was added to a solution of cyclohex-2-enone (10 g, 0.104 mol) in 500 mL of dichloromethane at 0° C. followed by the dropwise addition of 10 mol % TFA dissolved in 2 mL of dichloromethane. The reaction mixture was stirred at room temperature overnight and was quenched with 50 mL of saturated NaHCO3. The organic layer was washed with 500 mL of brine, dried with MgSO4 and solvent was evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 2-45% ethylacetate-hexane gradient to afford the subtitle compound. (13.8 g, 60%). MS calculated for C15H19NO+H: 230, observed: 230.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:19]=[C:18]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:33])[C:9](=[O:34])[NH:8]2)(O)=[O:2].C(N1C=CN=C1)([N:37]1C=CN=C1)=O.N>O1CCCC1.C(OCC)(=O)C>[C:1]([C:4]1[S:5][CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[N:10]([C:14]1[CH:19]=[C:18]([S:20]([N:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=1[Cl:33])[C:9](=[O:34])[NH:8]2)(=[O:2])[NH2:37]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 5-carboxy-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (14 mg) in tetrahydrofuran (1 mL) was added 1,1′-carbonylbis-1H-imidazole (9 mg), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: methylene chloride/ methanol=10/1) to give the title compound (13 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4](F)[CH:3]=1.CS(CCO)(=O)=[O:15].[H-].[Na+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([OH:15])[CH:3]=1
Reactant: CS(=O)(=O)CCO
Reactant: CS(=O)(=O)c1ccc(Br)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Br)cc1O
Yield: 86 %

Procedure:
To 4-bromo-2-fluoro-1-methylsulfonyl-benzene (2 g, 7.9 mmol) in DMF (15 mL) is added 2-methanesulfonyl-ethanol (1.47 g, 11.85 mmol). Sodium hydride (948.16 mg, 23.71 mmol) is added in portions at 0° C. The reaction mixture is allowed to come to r.t. and is added dropwise into cooled aq. hydrochloric acid. The aq. layer is extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and concentrated. The crude residue is purified by reversed phase HPLC. Yield 86%, m/z 251/253[M+H]+, rt 0.42 min, LC-MS Method X018_S01.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:21])[CH3:10])[C:5]([Cl:29])=[CH:4][N:3]=1.O.[NH3:31]>>[NH2:31][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:21])[CH3:10])[C:5]([Cl:29])=[CH:4][N:3]=1
Reactant: N
Reactant: Cc1cccc2cc([C@H](C)Nc3nc(Cl)ncc3Cl)n(-c3ccccc3)c(=O)c12
Solvent: O
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)ncc3Cl)n(-c3ccccc3)c(=O)c12
Temperature: 150 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
A mixture of (S)-3-(1-(2,5-dichloropyrimidin-4-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5101) (85 mg, 0.20 mmol) in ammonia water (15 mL) in a sealed tube was stirred at 150° C. for 16 h. The solution was allowed to cool to room temperature and then partitioned between water (30 mL) and ethyl acetate (3×30 mL). The combined organic layer was washed with brine (2×20 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product, (S)-3-(1-(2-amino-5-chloropyrimidin-4-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (5102, compound 249 in Table 4) (40 mg, 49.6% yield) as a white solid.
Reaction SMILES: C([C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[C:16]=1OC)([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6]CC)=[O:5])#N.I>C(O)(=O)C>[CH2:9]([CH:3]1[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])[C:16]=2[O:5][C:4]1=[O:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Agent: I
Solvent: CC(=O)O
Product: CCCCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Yield: 47.8 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-octanoate (6.6 g), acetic acid (30 ml) and hydriodic acid (58%, 30 ml) was refluxed under heating for 48 hours. After cooling, acetic acid was distilled off under reduced pressure. To the residue was added water, and the mixture was extracted with diethyl ether. The extract was washed with water, aqueous sodium hydrogen sulfite, aqueous sodium bicarbonate and water in turn, dried and then evaporated under reduced pressure. The oily residue (4.5 g) was subjected to column chromatography on silica gel (80 g) and eluted with benzene to give oily 3-(n-hexyl)-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (2.5 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:15][N:14]([C:16]2[CH:27]=[CH:26][C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][CH:17]=2)[CH2:13]1.C(N(CC)CC)C>>[CH:23]([NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N:14]2[CH2:13][C:12](=[O:11])[CH2:15]2)=[CH:27][CH:26]=1)([CH3:25])[CH3:24]
Reactant: CC(C)NC(=O)c1ccc(N2CC(O)C2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)NC(=O)c1ccc(N2CC(=O)C2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (1.05 mL, 12.4 mmol) in dichloromethylene (20 mL) was added dropwise dimethyl sulfoxide (1.71 mL, 24.1 mmol). The mixture was stirred at −78° C. for 10 min. Then a suspension of 4-(3-hydroxyazetidin-1-yl)-N-isopropylbenzamide (1.72 g, 7.34 mmol) in dichloromethylene (20 mL) was added. The mixture was stirred at −78° C. for 1 h, and then triethylamine (7.04 mL, 50.5 mmol) was added. The mixture was stirred at −78° C. for an additional 1.5 h. The mixture was washed with aq. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The precipitates were washed with ether and collected by filtration to afford the desired product (1.32 g, 77%) which was directly used in the next step without further purification. LCMS cacld. for C13H17N2O2 (M+1)+: m/z=233.1. Found: 233.1.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][CH3:16])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=O)C>O.NN>[CH3:16][O:15][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([NH2:4])=[CH:10][CH:9]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(C(=O)O)c1ccc(NC(C)=O)cc1
Agent: NN
Solvent: O
Product: COC(C(=O)O)c1ccc(N)cc1
Yield: 45.1 %

Procedure:
2-(4-Acetamidophenyl)-2-methoxyacetic acid (7.1 g, 31.8 mmol) was heated with hydrazine monohydrate (40 ml) for 16 hr, cooled and concentrated in vacuo. The resulting residual oil was purified by silica gel column chromatography (eluent 20-40% methanol in CH2Cl2) to give 2.6 g (45%) of (±)-2-methoxy-2-(4′-aminophenyl)-acetic acid 1H NMR (δ, 250 MHz, CD3OD): 3.27 (3H, s), 4.43 (1H, s), 6.66 (2H, d, 8.5 Hz), 7.18 (2H, d, 8.2 Hz).