Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[N:6]=1>C1(C)C=CC=CC=1>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: C[O-]
Reactant: Brc1cccc(Br)n1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(Br)n1
Temperature: 120 °C
Reaction time: 13 h

Procedure:
In an argon atmosphere, sodium methoxide (1.82 g) was added to 2,6-dibromopyridine (8.0 g) in toluene (120 mL), followed by stirring at 120° C. for 13 hours. Subsequently, sodium methoxide (0.728 g) was added to the mixture, followed by stirring at 120° C. for 6 hours. The mixture was cooled in air. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound in an oily substance (5.64 g, 89%).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[S:32][C:25]4[C:26]5[S:31][CH:30]=[CH:29][C:27]=5[S:28][C:24]=4[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][C:48](Cl)=[O:49])=[CH:43][CH:42]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:33]([O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:47][C:48]([NH:21][C:18]2[C:17]([C:22]3[S:32][C:25]4[C:26]5[S:31][CH:30]=[CH:29][C:27]=5[S:28][C:24]=4[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:49])=[CH:45][CH:46]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3cc4sc5ccsc5c4s3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2cc3sc4ccsc4c3s2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 20.9 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thieno[3,2-b:2′,3′-d]thiophen-2-yl)pyrazin-2-amine (7l) (370 mg, 746 μmol) and 4-(dimethylamino)pyridine (14.8 mg, 121 μmol) dissolved in anhydrous pyridine (15 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1). The resulting solid was recrystallized (n-hexane/ethyl acetate) to give Compound 11l (116 mg, 156 μmol, 20.9%) as a brown solid. Rf=0.19 (n-hexane/ethyl acetate=3/1); 1H NMR (400 MHz, DMSO-d6) δ 0.16 (s, 6H), 0.21 (s, 6H), 0.93 (s, 9H), 0.94 (s, 9H), 3.68 (s, 2H), 6.78-6.88 (AA′BB′, 2H), 6.94-7.06 (AA′BB′, 2H), 7.20-7.30 (AA′BB′, 2H), 7.47 (d, 1H, J=5.2 Hz), 7.65 (s, 1H), 7.75 (d, 1H, J=5.2 Hz), 8.06-8.14 (AA′BB′, 2H), 8.93 (s, 1H), 10.72 (s, 1H); IR (KBr, cm−1) 530, 602, 644, 700, 779, 837, 922, 1072, 1171, 1265, 1361, 1447, 1504, 1603, 1657, 2857, 2928, 2955, 3208.
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:42][C:43]([NH2:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[CH2:30][CH2:29]1>CCOC(C)=O>[NH2:45][C:43]([NH:42][C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][CH:31]2[CH2:32][CH2:33][N:28]([C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=3)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:29][CH2:30]2)[CH:41]=[CH:40][CH:39]=1)=[O:44]
Reactant: NC(=O)Nc1cccc(CCC2CCNCC2)c1
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(NC(N)=O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (228 mg) was added to an acetonitrile (5 ml) solution of 1-{3-[2-(4-piperidinyl)ethyl]phenyl}urea hydrochloride (185 mg) and TEA (0.2 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain methyl 5-({[4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidyl]carbonyl}oxy)nicotinate (183 mg).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]C1.[NH4+].[Cl-]>C1COCC1>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: BrC1CCCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
First, 0.96-M THF solution of phenyl magnesium bromide (1.25 mL, 1.2 mmol), various additives (1.2 mmol) shown in TABLE 1 below and bromocycloheptane (177 mg, 1.0 mmol) (shown by “1” in TABLE 1 below) were charged in a 50-mL glass tube equipped with a magnetic stirrer and cooled to −78° C. At this temperature, 0.1-M THF solution of FeCl3 (0.5 mL, 5 mol %) was added to the mixture. The resulting solution was put in an ice bath and stirred at 0° C. for 30 minutes. Saturated aqueous solution (0.5 mL) of NH4Cl was added to terminate the reaction. After conventional treatments, the amount of bromocyclopentane consumed and the yields of compounds produced (shown by “2,” “3” and “4” in TABLE 1 below) and biphenyl were determined by gas chromatography (internal standard (n-decane, 71 mg, 0.5 mmol)). The results are shown in TABLE 1.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C@H:3]([N:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]4[CH:31]=CC=C[CH:27]=4)(=[O:25])=[O:24])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[C:8]1=[O:32])[C:4]([OH:6])=[O:5].CC(C)[C@H](N1CC2C(=CC(C3C=CC(NS(C(C)C)(=O)=O)=CC=3)=CC=2)C1=O)C(OC)=O>>[CH3:1][CH:2]([CH3:33])[C@H:3]([N:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH:26]([CH3:31])[CH3:27])(=[O:25])=[O:24])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[C:8]1=[O:32])[C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)C(C)C)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)C(C)C)cc3)cc2C1=O
Yield: 49 %

Procedure:
The compound of example 96 was prepared analogous to compound of example 78 by hydrolysis of compound of example 95.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])(C)(C)C.FC(F)(F)C(O)=O.C([N:43](CC)CC)C.C[Si](N=C=O)(C)C>C(Cl)Cl.CCOC(C)=O>[NH:7]([CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[C:6]([NH2:43])=[O:5]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[Si](C)(C)N=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
{3-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-propyl}-carbamic acid tert-butyl ester (26 mg, 0.058 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 1 h. Solvent and excess TFA were removed in vacuo. To the residue were added CH2Cl2 (3 mL), triethylamine (0.080 mL, 0.58 mmol), and trimethylsilyl isocyanate (0.050 mL, 0.29 mmol), and the resulting mixture was stirred for 16 h. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 9.3 mg of the title compound. MS: (+) m/z 418.31 (M+Na).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)O1.[H-].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[C:16]1([C:4]2[C:6]3[C:5]4[C:25](=[CH:24][CH:28]=[CH:16][CH:4]=4)[CH2:26][C:2]=3[C:7]([C:8]#[N:9])=[C:6]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)oc1=O
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1Cc1ccccc1-2

Procedure:
A mixture of 2-oxo-6-phenyl-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (280 mg), indanone-2 (132 mg) and NaH (44 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 140-141° C.; ESIMS 351 (M++1); IR (KBr) 2219 cm−1 (CN); 13C NMR (75.53 MHz, CDCl3): δ 22.89, 24.96, 36.00, 52.15, 100.45, 116.08, 117.93, 120.78, 123.54, 125.06, 125.34, 126.97, 127.35, 127.42, 131.32, 138.85, 139.20, 140.94, 141.01, 149.06, 153.62.
Reaction SMILES: C(O[C:4](=[NH:20])[C:5]1[CH:10]=[CH:9][C:8]([S:11](=[O:19])(=[O:18])[NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)C.[NH2:21][NH2:22]>C(O)C>[S:14]1[CH:15]=[CH:16][N:17]=[C:13]1[NH:12][S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4]([NH:21][NH2:22])=[NH:20])=[CH:10][CH:9]=1)(=[O:19])=[O:18]
Reactant: NN
Reactant: CCOC(=N)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: CCO
Product: N=C(NN)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 4-(thiazol-2-ylsulfamoyl)-benzimidic acid ethyl ester (0.18 mmol) in ethanol (5 mL) was added hydrazine (0.1 mL) and the resulting mixture was stirred for 10 min. After the reaction mixture was concentrated in vacuo, it gave 4-(thiazol-2-ylsulfamoyl)-N-aminobenzamidine, which was used in next step without further purification. The crude 4-(thiazol-2-ylsulfamoyl)-N-aminobenzamidine was dissolved in THF and dichloromethane (10 mL, 1:1), and (3-chloro-phenyl)-acetyl chloride (0.36 mmol) and triethyl amine (0.9 mmol) were added. The mixture was stirred for 24 h before it was concentrated in vacuo. The mixture was diluted with AcOEt (30 mL) and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The solution of the residue in DMF and acetic acid (10 mL, 1:1) of was stirred at 80° C. for 24 h. After cooled to room temperature, the acetic acid was removed in vacuo and the residue was diluted with AcOEt (30 mL) and the organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by reverse phase HPLC to give 4-[5-(3-chloro-benzyl)-4H-[1,2,4]triazol-3-yl]-N-thiazol-2-yl-benzenesulfonamide (0.05 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
5-Chloroindole-2-carboxylic acid (391 mg, 2 mmol), tert-Butyl [(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]carbamate (497 mg, 2 mmol), DIPEA (350 μL, 2 mmol) and HOBT (270 mg, 2 mmol) were dissolved in DCM (10 mL), stirred for 5 mins, then EDCI (479 mg, 2.5 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (25 mL) was added and the organic solution washed with water (2×10 mL), brine (10 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (800 mg, 94%) as a pale brown foam.
Reaction SMILES: Cl[C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=1.[CH3:21][NH:22][CH:23]1[CH2:25][CH2:24]1.C(N(CC)CC)C>CO>[CH:23]1([N:22]([CH3:21])[C:2]2[C:3]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:4]=3[N:5]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:7]=2)[CH2:25][CH2:24]1
Reactant: CNC1CC1
Reactant: CCOC(=O)Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nc(N(C)C2CC2)c2c3c(sc2n1)CCCC3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ethyl 2-(4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate (7.0 g, 0.0225 mol) and N-methyl cyclopropyl amine (4.8 g, 0.0675 mol) was dissolved in methanol (200 ml). To this reaction mixture, triethyl amine (13.66 g, 0.135 mol) was added slowly at room temperature. The resulting reaction mixture was stirred at room temperature for 18 h. After completion of reaction it was concentrated under reduced pressure. The residue was dissolved in DCM (250 ml) and it was washed with water. Aqueous layer was extracted with DCM (250 ml). Organic extracts were combined and washed with brine. Separated organic layer was dried over anhydrous Na2SO4 and concentrated to get crude compound. It was purified by column chromatography by using 100-200 mesh silica gel and 10% EtOAc:hexane as eluent to give ethyl 2-(4-(cyclopropyl(methyl)amino)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-yl)acetate as a yellow solid. Yield—(6 g, 77.12%); 1H-NMR: (400 MHz, CDCl3); δ=4.20-4.10 (q, 2H), 3.88 (s, 2H), 3.1 (s, 3H), 2.90-2.86 (m, 3H), 2.84-2.83 (m, 2H), 1.93-1.87 (m, 2H), 1.77-1.71 (m, 2H), 1.41 (s, 1H), 1.26-1.23 (t, 3H), 0.72-0.68 (m, 2H), 0.45-0.41 (m, 2H); LC-MS [M+H]=345.9.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Cl:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[ClH:17]>C(O)C>[ClH:7].[ClH:17].[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][NH:6][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)CCN
Reactant: ClCCCN1CCCCC1
Agent: Cl
Solvent: CCO
Product: CC(C)CCNCCCN1CCCCC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 23.2 ml of isoamylamine and 16.17 g of 1-(3-chloropropyl)piperidine was heated to 120° C. for 2 hours. The reaction mixture was then dissolved in 100 ml of ethanol. To this ethanol solution was added 17 ml of conc. hydrochloric acid. The mixture was allowed to stand overnight at room temperature. The precipitated crystals were collected, washed with ethanol, and dried to give 14.70 g of 1-[3-(3-methylbutylamino)propyl]piperidine dihydrochloride as a white crystalline product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C@@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([S:16]CC2C(C)=CC(C)=CC=2C)[C@@H:11]1[O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].N.[Na].[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:35])[N:7]([C@@H:10]1[CH2:15][CH2:14][CH2:13][C@@H:12]([SH:16])[C@@H:11]1[O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[CH2:8][CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CCC[C@@H](SCc2c(C)cc(C)cc2C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCC[C@@H](S)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of [(1R,2R,3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-(2,4,6-trimethyl-benzylsulfanyl)-cyclohexyl]-ethyl-carbamic acid tert-butyl ester+(1S,2S,3S) diastereomer (1.20 g, 2.30 mmol) in 10 ml of tetrahydrofuran and 20 ml of liquid ammonia was treated at −78° C. under an argon atmosphere with sodium (106 mg, 4.60 mmol) and stirred at −78° C. for one hour. Then solid ammonium chloride was added and the reaction mixture was warmed to room temperature, diluted with tetrahydrofuran and flushed with nitrogen. The residual mixture was filtered and concentrated under reduced pressure to yield crude [(1R,2R,3R)-2-(tert-butyl-dimethyl-silanyloxy)-3-mercapto-cyclohexyl]-ethyl-carbamic acid tert-butyl ester+(1S,2S,3S) diastereomer (quantitative yield) which was directly used for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:17]([O:19]CC)=[O:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].Cl>CCO.O>[CH2:1]([O:3][C:4]([C:6]1([C:17]([OH:19])=[O:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(C(=O)O)CN(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Azetidine-1,3,3-tricarboxylic acid 1-tert-butyl ester 3,3-diethyl ester (1.2 g; 0.4 mmol) in EtOH (12 ml) is cooled to 5° C. under stirring and combined with NaOH (60 mg; 0.04 mmol) in water (4 ml). The reaction mixture is left at room temperature for 1 hour, heated to 50° C. for 5 minutes, poured on brine, acidified with 2N HCl and extracted with TBME three times. The reaction mixture is extracted with TBME three times, the organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as colorless crystals. 1H-NMR (400 MHz; DMSO-d6: 13.58 (bs, 1H); 4.20 (q, 2H); 4.12 (bs, 4H); 1.39 (s, 9H); 1.21 (t, 3H). MS (m/z) ES+: 274 (30; MH+); 174 (100).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].F[C:22](F)(F)[C:23]([OH:25])=O.C(Cl)Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC.C(Cl)Cl.O>[NH2:14][C@@H:13]([C@H:23]([OH:25])[CH3:22])[C@@H:17]([OH:18])[C:16]#[C:15][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1/[C:5](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:6](=[O:11])[NH:7]2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@H](O)[C@@H](N)[C@@H](C)O)c21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Using Method C above, 4R-(1S-hydroxy-prop-2-ynyl)-2,2,5R-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.2 g, 0.65 mmol) (Example 105A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (30 mg) (Aldrich) and CuI (6 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h. To the resulting compound in CH2Cl2 (10 mL) was added a 1:1 mixture of trifluoroacetic acid/CH2Cl2 (10 mL) and 5 drops of water at 0° C. and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with conc. NH4OH (10 mL) and diluted with EtOAc. The organic layer was washed with brine and dried with MgSO4. The product was purified via flash column chromatography (10% MeOH in CH2Cl2). (Yield 30 mg, 30%).
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]1([CH2:23][S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:24]([CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:26])=[O:25])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)Cc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.35 g of phenylmethanesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 25 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. After neutralization with concentrated hydrochloric acid the mixture was concentrated and the aqueous residue was extracted twice with ethyl acetate. The organic phases were combined, dried with magnesium sulphate and freed from solvent. The residue was chromatographed on 30 g of Kieselgel 60 with ethyl acetate/hexane (1:2) as the eluent. The product-containing fractions were concentrated. Recrystallization of the residue from 5 ml of ethyl acetate yielded 60 mg of N-[4-(3-nitro-phenyl)-thiazol-2-yl]-C-phenyl-methanesulfonamide as colorless crystals.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>CO>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1ccc(OCCCCBr)cc1
Temperature: 70 °C
Yield: 17.9 %

Procedure:
To a solution of hydroquinone (2.0 g, 18.2 mmol) in MeOH (20 mL), KOH (1.0 g, 18.2 mmol) was added. Then, 1,4-dibromobutane (2.7 mL, 22.7 mmol) was added dropwise over 10 min. After the addition was complete, the mixture was refluxed for 12 hours at 70° C. The reaction mixture was concentrated and quenched with water (100 mL), and then the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated to give a colorless oil, which was purified by column chromatography to isolate the intermediate 12a (0.8 g, 3.26 mmol, 18% yield). 1H NMR (CDCl3, 400 MHz) δ 6.78 (s, 4H), 4.53 (s, 1H), 3.95 (t, J=6 Hz, 2H), 3.52 (t, J=6.8 Hz, 2H), 1.86-2.15 (m, 4H).