Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:25][CH:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH2:28][CH2:27]4)[C:15]=3[C:14]1=2)[C:10]#[N:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:38][Li].O.OO>CO>[Si:1]([O:8][CH:9]([CH2:12][C@H:13]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:25][CH:26]4[CH2:27][CH2:28][CH:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)[CH2:30][CH2:31]4)[C:15]=3[C:14]1=2)[C:10]([NH2:11])=[O:38])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: [Li]O
Reactant: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: OO
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC(C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21)C(N)=O
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a solution of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanenitrile (300 mg, 0.55 mmol, 1.00 equiv) in methanol (20 mL) was added LiOH.H2O (47 mg, 1.12 mmol, 3.55 equiv) and H2O2 (30%, 0.8 mL). The solution was stirred for 2 hr in a water/ice bath. After completion, the reaction was quenched by the addition of 30 mL of saturated aqueous Na2SO3 and extracted with 3×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, purification by column chromatography on silica gel with dichloromethane/methanol (20:1) afforded the 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (197 mg, 64%) as a colorless oil. MS (ES): m/z 561 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CS(N1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=O)=O>>[NH:35]1[C:36]2[C:37](=[C:4]([C:2]3[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:5]=[CH:6][CH:8]=2)[CH:33]=[CH:34]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Via 2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared from 1-methanesulfonyl-piperazine
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:26][CH:27]([OH:31])[CH2:28][O:29][CH3:30].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.O>[CH3:30][O:29][CH2:28][CH:27]([OH:31])[CH2:26][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: COCC(O)CCl
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCC(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 144 h
Yield: 104.4 %

Procedure:
To a stirred solution of pyrazole-4-boronic acid pinacol ester (0.25 g, 1.29 mmol) in THF (5 mL) was added a solution of sodium bis(trimethylsilyl)amide (0.71 mL, 2M in THF, 1.42 mmol), followed by 1-chloro-3-methoxy-2-propanol (0.24 g, 2.58 mmol). The reaction mixture was stirred in a sealed vial at 90° C. for 6 days. Additional 1-chloro-3-methoxy-2-propanol (0.24 g, 2.58 mmol) was added, followed by triethylamine (0.35 mL, 2.60 mmol). The reaction mixture was stirred at 90° C. for 3 days, then cooled to r.t. Water (2 mL) and EtOAc (5 mL) were added. The organic fraction was separated, washed with H2O (2×2 mL), then brine (2 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (0.38 g, 96%) as an orange oil that was used without further purification. LCMS (ES+) 283.0 (M+H)+, RT 2.52 minutes (Method 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[C:36]1[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:24]=[CH:23][C:22]=1[C:36]1[CH:41]=[N:40][C:39]([NH2:42])=[N:38][CH:37]=1
Reactant: O=C(c1cc(C(F)(F)F)ccc1Br)N1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3C(=O)N3CCOCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (2-bromo-5-(trifluoromethyl)phenyl)(morpholino)methanone and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C22H18F4N4O2, 446.14; m/z found, 447.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.65-8.58 (d, J=1.3, 2H), 7.91-7.85 (dd, J=8.3, 1.9, 1H), 7.78-7.76 (m, 1H), 7.76-7.73 (d, J=8.1, 1H), 7.71-7.63 (m, 1H), 7.46-7.43 (dd, J=2.7, 1.8, 1H), 7.43-7.41 (dd, J=6.2, 1.7, 1H), 3.72-3.60 (m, 2H), 3.60-3.52 (m, 1H), 3.46-3.39 (m, 1H), 3.37-3.33 (m, 1H), 3.16-3.09 (m, 1H), 2.92-2.77 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])O[C:11]([CH3:13])=[N:12][C:7]=2[CH:6]=[C:5]([O:15][CH3:16])[CH:4]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][CH3:16])[CH:6]=[C:7]2[C:8]=1[C:9](=[O:14])[N:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[C:11]([CH3:13])=[N:12]2
Reactant: COc1cc(OC)c2c(=O)oc(C)nc2c1
Reactant: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2c(C)nc3cc(OC)cc(OC)c3c2=O)cc1
Temperature: 60 °C
Yield: 13.7 %

Procedure:
To a mixture of 135.5 mg (0.612 mmol) of the benzoxazinone prepared in Example 6 and glacial acetic acid (2 mL), p-anisidine (0.735 mmol) was added and the reaction mixture was heated to 60° C. for 24 hrs. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the product as a yellow oil (13.7% yield).
Reaction SMILES: [S:1]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:11])[NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19].O>CN(C)C=O>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][N:4]1[C:5](=[O:11])[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[S:1][CH2:2][CH2:3]1)[CH3:19]
Reactant: O=C1NCCSc2sccc21
Reactant: CCOC(CBr)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CN1CCSc2sccc2C1=O)OCC

Procedure:
To a solution of 8.0 g of 2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 160 ml of N,N-dimethylformamide was added 6.3 g of potassium t-butoxide with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. Then to the mixture was added 8.4 ml of bromoacetaldehyde diethyl acetal under ice-cooling. The mixture was stirred for 5 hours at room temperature and water was added thereto and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel using and chloroform and methanol (98.8:0.2) as an eluent to give 6,9 g of 4-(2,2-diethoxyethyl)-2,3-dihydrothieno[3,2-f]1,4-thiazepin-5(4H)-one as a pale yellow oil. To the solution of thus obtained 6.7 g of 4-(2,2-diethoxyethyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 150 ml of tetrahydrofuran was added 20 ml of 10% hydrochloric acid and the mixture was allowed to stand for 20 hours at room temperature, and then poured into water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off to give 4.4 g of 2,3,4,5-tetrahydro-5-oxothieno[3,2-f]-1,4-thiazepin-4-acetaldehyde as a pale yellow oil.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NCC1CCOCC1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: c1ccc2c(c1)ncn2-c1nc(NCC2CCOCC2)nc2[nH]cnc12
Temperature: 120 °C

Procedure:
250 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 531 mg μl of 4-aminomethyl-tetrahydropyran, and the mixture is then heated at 120° C. for approximately 2 days. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. 142 mg of expected product are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:37])([F:36])[C:11]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:33]([N:32]([CH2:31][C:11]([OH:30])([CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10]([F:37])([F:36])[F:9])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH2:34][CH3:35]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1ccsc1
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 11 from 3-thiophenecarboxylic acid and 1,1,1-trifluoro-3-[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:13]CO[CH2:10]1)C1C=CC=CC=1.CC(N)(C)CN>>[O:39]=[S:30]1(=[O:38])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:16]([NH:15][CH2:14][C:9]([CH3:10])([NH2:8])[CH3:13])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH2:28][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Agent: CC(C)(N)CN
Product: CC(C)(N)CNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccccc12

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using and 2,4-dichloroquinoline 2,3,4,5-tetrahydro-1,4-benzothiazepine) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.02-7.93 (m, 1 H), 7.87 (s, 2 H), 7.64-7.57 (m, 1 H), 7.56-7.48 (m, 1 H), 7.42 (s, 2 H), 7.19-7.09 (m, 1 H), 6.11 (s, 1 H), 5.23-5.07 (m, 2 H), 3.63-3.51 (m, 2 H), 3.37 (s, 2 H), 3.33 (m, 2 H), 3.28 (s, 2 H), 1.26 (s, 6 H).
Reaction SMILES: [NH2:1][C:2](=[N:26][N+:27]([O-:29])=[O:28])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:23]([OH:25])=O)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:10].[NH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][CH:36]=1)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CO>[NH2:30][C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:23](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:26][N+:27]([O-:29])=[O:28])[NH:8][C:9]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[O:10])=[CH:37][CH:36]=1)=[O:32]
Reactant: NCc1ccc(CNC(N)=O)cc1
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)OCc1ccc2ccccc2c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Product: NC(=O)NCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)OCc2ccc3ccccc3c2)cc1
Yield: 32 %

Procedure:
Prepared analogously to Example 69a) from (R)-N5 -[amino(nitroimino)methyl]-N2 -[(2-naphthyl)methoxycarbonyl]-ornithine, 4-(aminocarbonylaminomethyl)benzenemethanamine and TBTU in a yield of 32% of theory. Colourless crystals, Mp. 155-160° C. (Methanol/glacial acetic acid 20/1, v/v).
Reaction SMILES: [Na].S(N[N:13]=[CH:14][C:15]1C=CC=C[C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(C1C=CC(C)=CC=1)(=O)=O.[C:28]([O:32][C:33](=[O:37])NC=C)([CH3:31])([CH3:30])[CH3:29].O1CCOCC1.C(OC)(C)(C)C>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[C:28]([O:32][C:33](=[O:37])[NH:13][C@@H:14]1[CH2:15][C@@H:16]1[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2-c2ccc(F)cc2)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 215.4 %

Procedure:
4-Fluorophenyl benzaldehyde-tosylhydrazone sodium salt (786 mg, 2.5 mmol), N-vinyl-carbamic acid tert-butyl ester (1.432 g, 10 mmol) and benzyltriethylammonium chloride (57 mg, 0.25 mmol) were covered with dioxane (11 ml) under argon. Rh2(OAc)4 (11 mg, 0.025 mmol) was added and the suspension stirred at room temperature for 15 minutes. The slurry became thick and difficult to stir so a further 4 ml of dioxane was added. The mixture was stirred at 75° C. for 2 hours, then shaken between tBuOMe and water. The organic phase was washed with water and NaCl (satd), dried over MgSO4 and evaporated to yield a brown viscous oil (1.353 g), which was chromatographed on silica to yield 2-(4-fluoro-phenyl)-cyclopropyl-carbamic acid tert-butyl ester 369 mg (59%, m.p. 117-118° C.) cis and 125 mg (20% m.p. 102-105° C.) trans.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([N+:24]([O-:26])=[O:25])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])=[C:8]2[C:20]([O:22][CH3:23])=[O:21].[CH3:27]I.OS([O-])(=O)=O.[Na+]>CN(C)C=O>[CH3:3][O:4][C:5]1[C:6]([N+:24]([O-:26])=[O:25])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:27])[C:9]([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])=[C:8]2[C:20]([O:22][CH3:23])=[O:21]
Reactant: CI
Reactant: COC(=O)C=Cc1[nH]c2ccc(OC)c([N+](=O)[O-])c2c1C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1c(C(=O)OC)c2c([N+](=O)[O-])c(OC)ccc2n1C
Temperature: 60 °C

Procedure:
This synthesis was carried out under an atmosphere of dry N2. To a stirred suspension of NaH (2.9 g) in dimethylformamide (145 ml) were added 9.34 g (28 mmol) methyl 5-methoxy-3-methoxycarbonyl-4-nitro-2-indoleacrylate (15). Thereupon the whole mixture was heated at 45°-50° C. When the evolution of H2 had ceased methyliodide (25 ml) was added to the dark red solution. During an additional (1 h) heating of the reaction mixture at 60° C., the colour of the solution turned to yellow. After cooling this mixture was poured into cold (0° C.) 10% NaHSO4 aq. Yellow crystals separated, which were collected by filtration, washed with water and ethanol, and finally dried in vacuo at 50°-60° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([O:1][CH2:2][C@@H:3]([NH:11][C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCO1
Reaction time: 1 h
Yield: 49 %

Procedure:
At 0° C., tert-butyl (2S)-1-hydroxy-3-(tetrahydro-2H-pyran-2-yl)propan-2-ylcarbamate (1.41 g, 5.44 mmol) in CH2Cl2 (50 mL) was treated with Et3N (2.3 mL, 16.3 mmol) followed by methanesulfonyl chloride (1.1 mL, 13.6 mmol). The reaction was allowed to stir for 1 h and quenched with water. The organic layer was washed with satd aq NaHCO3 and brine, dried over Na2SO4, and filtered. After removal of solvent, the crude material was purified using chromatography on silica gel (EtOAc/Hex) to afford (2S)-2-(tert-butoxycarbonylamino)-3-(tetrahydro-2H-pyran-2-yl)propyl methanesulfonate (0.90 g) as a solid. MS m/z 360 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][NH2:25].[CH3:26][O:27][CH2:28][CH2:29][CH:30]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:20])=[O:19])=[CH:14][CH:13]=1)/[C:6]([CH3:21])=[C:5]2[CH2:22][CH2:23][O:24][N:25]=[CH:30][CH2:29][CH2:28][O:27][CH3:26]
Reactant: COCCC=O
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccc(S(C)=O)cc1
Product: COCCC=NOCCC1=C(C)/C(=C/c2ccc(S(C)=O)cc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-methylsulfinylphenyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-methoxypropanal by the method of Example 1.
Reaction SMILES: [F:1][C:2]1[C:7](Cl)=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C([Mg:16][Br:17])(C)C>>[F:1][C:2]1[C:7]([Mg:16][Br:17])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: CC(C)[Mg]Br
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F

Procedure:
The process according to claim 8 wherein the step (a) pentafluorochlorobenzene is reacted with isopropylmagnesium bromide in a mole ratio range from about 1:1 to 2:1 in a dialkyl ether solvent to provide pentafluorophenylmagnesium bromide.
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([CH3:10])=[CH:9][N:4]2[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:2]2[S:6][C:5]3=[N:7][C:8]([CH3:10])=[CH:9][N:4]3[N:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1cn2nc(Br)sc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccc(-c2nn3cc(C)nc3s2)cc1OC
Temperature: 130 °C
Yield: 50 %

Procedure:
To a mixture of 2-bromo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.550 g, 2.522 mmol, 1 eq), 3,4-dimethoxyphenylboronic acid (0.551 g, 3.026 mmol, 1.2 eq) and Pd(dppf)Cl2.DCM (0.209 g. 0.252 mmol, 0.1 eq) in DME (3 mL) was added K2CO3 (1 mL, sat. aq). The mixture was heated in the microwave oven (130° C., 1 h), cooled to RT, diluted with DCM, washed with water, dried (Na2SO4) and concentrated. The residue (yellow solid, 0.720 g) was purified by automated flash chromatography (SiO2, DCM/0-40% MeOH) to give the desired product (yellow solid, 0.347 g, 50%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.77 min, [M+H]+ m/z 276.1.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]/[C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.Cl.[O:26]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]1>>[O:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:4]([C:6]2[S:10][C:9](/[CH:11]=[CH:12]/[C:13]3[C:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:8][CH:7]=2)=[O:5])[CH2:27]1
Reactant: N[C@H]1CCOC1
Reactant: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ncc(C(=O)N[C@H]2CCOC2)s1
Yield: 89 %

Procedure:
As described for example 63b, 2-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-thiazole-5-carboxylic acid ethyl ester (50 mg, 0.15 mmol) was converted, using (S)-tetrahydrofuran-3-amine HCl instead of 4-aminotetrahydropyran, to the title compound (50 mg, 89%) which was obtained as a white solid. MS: m/e=382.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]1C=CC=C[CH:18]=1.Cl>O>[C:18]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:17]
Reactant: c1ccncc1
Reactant: Clc1ccc(-c2coc3ccccc23)cc1
Agent: Cl
Solvent: O
Product: N#Cc1ccc(-c2coc3ccccc23)cc1

Procedure:
A mixture of 45.2 g. (0.198 mole) of 3-(4-chlorophenyl)benzofuran, 22.2 g. (0.248 mole) of cuprous cyanide and 15 ml. of pyridine is heated to 220° C. and maintained at this temperature for one day. The mixture is then poured into a solution of 47.5 g. of ferric chloride, 30 ml. of concentrated hydrochloric acid and 135 ml. of water with stirring. The mixture is stirred with heating below its boiling point for 1 hour. The aqueous portion is removed, and the organic portion is mixed with 1.2 liter of benzene, and the mixture is stirred for 1 hour. The mixture is then filtered. The filtrate is washed with 6 N hydrochloric acid, water, 10 percent sodium hydroxide solution and saturated sodium chloride solution, then dried over magnesium sulfate. The benzene solution is then evaporated to provide a dark oil which solidifies to provide 3-(4-cyanophenyl)benzofuran. The infrared spectrum of the product is consistent with the assigned structure.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]1>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([N:31]4[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]4)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Reactant: CC(C)(O)C1CCNCC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure K, 2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid was coupled with 2-(piperidin-4-yl)propan-2-ol to give 569. LCMS m/z: 533.3 (M+H+)
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1C2C(=CC=CC=2B(O)O)[CH:18]=[CH:17][CH:16]=1>>[N:15]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][C:1]=2[C:7]2[N:12]=[C:11]([CH:13]=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc2cccnc12
Reactant: O=Cc1cccc(-c2ccccc2)n1
Product: O=Cc1cccc(-c2cccc3cccnc23)n1

Procedure:
Precursor (F) was prepared following the same procedure as that used to prepare precursor (A) except that 216 mg (1.2 mmol) of 8-quinolineboronic acid were used as reagent. 232 mg of precursor (F) were obtained as pale yellow solid with a yield of 99%.