Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C1COCC1>[C:36]([NH:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:33][C:32]6[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=6)[C:26]5=[O:34])[C:20]=4[CH3:35])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(CN)ccc4c23)cccc1N1Cc2ccccc2C1=O
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3cccc(N4Cc5ccccc5C4=O)c3C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A solution of crude 7-(aminomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 33-1, 60 mg, 0.065 mmol) and TEA (23 μL, 0.163 mmol) in THF (1.3 mL) was treated with acetic anhydride (7.4 μL, 0.078 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and the residue was purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated to provide 7-(acetamidomethyl)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as an off-white solid (12 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 11.51 (1H, s), 8.29-8.45 (1H, m), 8.18 (1H, br. s.), 8.01 (1H, d, J=7.9 Hz), 7.81 (1H, d, J=7.5 Hz), 7.69 (2H, d, J=4.0 Hz), 7.60-7.65 (2H, m), 7.57 (1H, ddd, J=7.9, 4.2, 4.0 Hz), 7.50 (2H, t, J=7.8 Hz), 7.34 (1H, dd, J=7.7, 1.1 Hz), 6.94-7.06 (2H, m), 6.87 (1H, dd, J=8.3, 1.4 Hz), 4.90-5.04 (2H, m), 4.35 (2H, t, J=5.2 Hz), 1.89 (3H, s), 1.84 (3H, s). Mass spectrum m/z 503.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[CH:28]=[CH:27][N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:13]([C:24]3[CH:28]=[CH:27][NH:26][CH:25]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cc[nH]c2)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
305 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)-6-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]pyrimidine-2,4-diamine was dissolved in 3 ml of tetrahydrofuran, and 0.86 ml of 1M tetrabutylammoniumfluoride/tetrahydrofuran solution was added under ice water cooling, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was added with water. The solution was subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 199 mg of the objective compound as pale brown powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1ccccn1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccccn1

Procedure:
A mixture of 25 g. of 2-acetylpyridine and 35 ml. of N,N-dimethylformamide dimethylacetal is refluxed for 16 hours. The mixture is cooled and filtered to give 3-dimethylamino-1-(2-pyridyl)-2-propen-1-one as crystals, m.p. 127°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1.C(P(O)(=O)O)CC.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[O:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([NH:19][C:26]([C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)=[O:27])[CH2:17][CH2:18]1
Reactant: N[C@H]1CC[C@H](Oc2ccnc3c(Br)cccc23)CC1
Reactant: Cc1cc(C(=O)O)no1
Agent: CCCP(=O)(O)O
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(C(=O)N[C@H]2CC[C@H](Oc3ccnc4c(Br)cccc34)CC2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-4-[(8-Bromoquinolin-4-yl)oxy]cyclohexylamine (321 mg, 1.0 mmol), and 5-methylisoxazole-3-carboxylic acid (153 mg, 1.2 mmol) were put in pyridine (4.0 mL) and propanephosphonic acid cycloanhydride (637 mg, 2.0 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water was added until a precipitate formed. After a further 10 minutes the precipitate was filtered off with suction and washed with water. After drying, the desired compound was obtained at 92% yield (400 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][C:7]1=O)=O.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].N1CCCCC1>C(O)C>[C:14]([C:16]1[C:17](=[O:18])[NH:19][C:4]([CH2:3][O:2][CH3:1])=[C:6]2[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH2:11]2)#[N:15]
Reactant: N#CCC(N)=O
Reactant: COCC(=O)C1CC(C)CCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COCc1[nH]c(=O)c(C#N)c2c1CC(C)CC2

Procedure:
Crude 2-methoxyacetyl-4-methylcyclohexanone, 3.7 g, 1.68 g of cyanoacetamide and 1 ml of piperidine were mixed with 50 ml of ethanol followed by heating to reflux for 4 hours. The precipitated crystals were taken out by filtration and purified to give 1.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methoxymethyl7-methyl-3-oxoisoquinoline.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18]>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[O:13][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COc1ccc(C=O)cc1O
Product: COc1ccc(C=O)cc1OCc1ccc2ccccc2c1
Yield: 50 %

Procedure:
2-Bromomethylnaphthalene was reacted with 3-hydroxy-4-methoxybenzaldehyde using the conditions described in Example 1 to give 4-methoxy-3-(naphth-2-ylmethoxy)benzaldehyde in 50% yield, m.p. 80° C. Following the procedure described in Note k. above the product so obtained was reacted with thiazol-2-yl-lithium to give 2-[4-methoxy-3-(naphth-2-ylmethoxy)-α-hydroxybenzyl]thiazole as an oil in 62% yield; that product was oxidised with sodium dichromate to give 4-methoxy-3-(naphth-2-ylmethoxy)phenyl 2-thiazolyl ketone in 58% yield, m.p. 149°-150° C.; and the product so obtained was reacted with ethylmagnesium iodide to give the required starting material in 45% yield, m.p. 80° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])C)C=O)(=[O:3])[CH3:2].O[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].B(F)(F)F.CCOCC>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[O:12][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(=[O:27])[CH3:26]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Reactant: CCOC(=O)CCCCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCCCCO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.8 %

Procedure:
To mannose pentaacetate (10.00 g, 25.64 mmol) dissolved in 60 mL of CH2Cl2, ethyl 6-hydroxyhexanoate (8.3 mL, 51.28 mmol) was added at room temperature and then BF3.Et2O at 0° C. After 4 days under stirring at room temperature, the reaction mixture was washed twice with NaHCO3 (2×20 mL) and then with brine (20 mL). The organic layer was dried (MgSO4) and concentrated under vacuum. Compound 1 (7.14 g, 57%) was obtained after column chromatography on silica gel (hexane/AcOEt; 6:4).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][O:7][CH:8]([CH3:10])[CH3:9].NC(N)=[S:13].[OH-].[Na+]>O>[CH:8]([O:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2][SH:13])([CH3:10])[CH3:9]
Reactant: NC(N)=S
Reactant: CC(C)OCCC=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)OCCC=CCS
Reaction time: 0.5 h

Procedure:
A mixture of 8.1 g (0.05 mol) of 1-chloro-5-isopropoxy-2-pentene, 3.8 g (0.05 mol) of thiourea, and 5 cc of water are heated to 98° during the course of 35 minutes and stirred at this temperature for 30 minutes. The homogeneous reaction mixture is cooled to 60° and 10 cc (0.05 mol) of 5N caustic soda solution are added dropwise at this temperature. The mixture which again has rendered heterogeneous is heated to 100° with stirring, is cooled after 5 minutes and poured on water The reaction mixture is extracted with ether, the ether extract is washed with saturated salt solution, is dried with sodium sulphate and the ether is evaporated. The residue is fractionated at 16 mm, whereby the 5-isopropoxy-2-penten-1-thiol is obtained as malodorous oil which is uniform according to gas-chromatography; it has a B.P. of 87°-89°/16 mm. nD20 = 1.4696.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:15](=[O:25])[NH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.C(#N)C.[O-2].[O-2].[Mn+4]>[O:25]=[C:15]1[NH:14][CH:13]=[CH:12][C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=3)[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]1=2
Reactant: O=c1[nH]ccc2nc(-c3ccc(CO)cc3)c(-c3ccccc3)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(-c2nc3cc[nH]c(=O)c3cc2-c2ccccc2)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(hydroxymethyl)phenyl]-3-phenyl-1,6-naphthyridin-5(6H)-one (316 mg, 0.96 mmol) in chloroform (15 mL) and acetonitrile (15 mL) was added activated manganese dioxide (903 mg, 10 mmol) which was warmed at 60° C. for three hours. The warm suspension was filtered, rinsed with chloroform and the solvents removed in vacuo. The residue was triturated with diethyl ether and the suspension filtered to give the title compound as a pinkish solid. 1H-NMR (500 MHz, CDCl3): δ 10.20 (1H, s), 9.89 (1H, br s), 8.73 (1H, s), 7.81 (2H, d, J=8 Hz), 7.61 (2H, d, J=8 Hz), 7.35-7.38 (1H, m), 7.30-7.32 (2H, m), 7.21-7.22 (2H, m), 6.91 (1H, d, J=7.3 Hz). m/e (m+1): 327.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC(C(=O)CC2C=CN=CC=2)=C([F:50])C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[CH:18][N:17]([CH3:26])[N:16]=2)=[C:13]([F:50])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccncc1)c1ccc(OCc2ccccc2)cc1F
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2)n1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccccc3)cc2F)n1

Procedure:
Following the procedure for the preparation of 4-[3-(4-Benzyloxy-phenyl)-1-methyl-1H-pyrazol4-yl]-pyridine but substituting 1-(4-Benzyloxy-2-fluoro-phenyl)-2-pyridin4-yl-ethanone provided the title compound. MS: (M+H m/z=360.1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[NH:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[N:22]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[C:29](=[O:31])[CH3:30])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Nc2ccncc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 8 h

Procedure:
4-tert-Butyl-N-[4-chloro-2-(pyridin-4-ylamino)-phenyl]-benzenesulfonamide (103 mg, 0.25 mmol) dissolved in DCM (5 mL) was treated with acetic anhydride (26 mg, 0.25 mmol) and triethylamine (51 mg, 0.5 mmol), and the reaction mixture was allowed to stir overnight. The volatiles were evaporated and the product was purified by HPLC to afford the title compound. MS: (M+H)/z=458.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[Cl:18][C:19]1[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[C:21](Cl)[N:20]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:18][C:19]1[N:20]=[C:21]([N:4]2[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH:3]2[C:7]([O:9][CH3:10])=[O:8])[CH:22]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[N:24]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2C(=O)OC)nc(Cl)n1
Temperature: 50 °C

Procedure:
A mixture of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (5.133 g, 21.01 mmol), methyl 2,6-dichloropyrimidine-4-carboxylate (4.354 g, 21.03 mmol), and iPr2NEt (4.0 mL, 23.0 mmol) in acetonitrile (50 mL) was heated at 50° C. for 4 h. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 20-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to give 1-tert-butyl 3-methyl 4-(2-chloro-6-(methoxycarbonyl)pyrimidin-4-yl)piperazine-1,3-dicarboxylate as a very pale yellow powder (6.626 g, 15.97 mmol, 76% yield). LC/MS: m/z=415.2 [M+H]+.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[N:21][NH:22][CH:23]=1.O.Cl>CN(C)C=O>[CH3:14][O:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[N:21][N:22]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:23]=1
Reactant: COCCOc1cn[nH]c1
Reactant: CSc1nc2ccccc2c(=O)[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1cnn(-c2nc3ccccc3c(=O)[nH]2)c1
Yield: 58.5 %

Procedure:
96 g (0.5 mole) of 2-methylthio-4(3H)-quinazolinone are stirred in 250 ml of dimethylformamide with 142 g (1 mole) of 4-(β-methoxy-ethoxy)pyrazole at the reflux temperature for 40 hours. After cooling, 2.5 litres of water are added and a pH value of 3 is established with hydrochloric acid. The crude product which separates out (97.3 g of melting point 119°-24°) is recrystallized from isopropanol. 83.8 g of 2-(4-β-methoxyethoxy-1H-pyrazol-1-yl)-4(3H)-quinazolinone of melting point 125° to 127° C. are obtained.
Reaction SMILES: [C:1]1([N:7]2[C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:10](=[O:17])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[O:17]=[C:10]1[C:11]2([CH2:12][CH2:13][N:14]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:15][CH2:16]2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9]1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A solution of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (10 g, 43.23 mmol, 1 equiv) in dichloromethane was treated with pyridine (6.99 ml, 86.46 mmol, 2 equiv) at 0° C. This was followed by the slow addition of benzyl chloroformate (6.39 ml, 45.4 mmol, 1.05 equiv). The reaction was stirred at ambient temperature for 16 h. The mixture was partitioned between dichloromethane and 10% citric acid followed by washes with water and brine. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to afford benzyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an off-white powder (12.5 g, 79%); MS for C21H23N3O3 m/z 366.18 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2C(OC(C)(C)C)=O)[O:9][C:8](=[O:28])[NH:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][NH:12]2)[O:9][C:8](=[O:28])[NH:7]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2Cc3ccccc3CN2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
A solution of (R)-tert-butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (6), 400 mg) in CH2Cl2 (20 mL) was treated with TFA (10 mL). This reaction mixture was stirred at rt for 3 h. The mixture was then concentrated in vacuo with addition of toluene. The residue was partitioned between ethyl acetate (200 mL) and aqueous sodium carbonate solution. The organic phase was washed again with aqueous sodium carbonate solution, H2O, and dried (Na2SO4), and concentrated in vacuo to give 320 mg (100% yield) of the title compound: 1H NMR (CDCl3, 500 MHz) δ 2.62 (1H, dd, J=10, 15 Hz), 2.66 (1H, dd, J=10, 15 Hz), 3.10 (1H, dd, J=5, 15 Hz), 3.24 (1H, dt, J=5, 10 Hz), 3.33 (1H, dd, J=5, Hz), 3.98 (2H, s), 4.05 (1H, m), 4.39 (1H, m), 5.64 (1H, s), 6.70 (1H, m), 6.76 (2H, d, J=10 Hz), 7.02 (1H, t, J=5 Hz), 7.12-7.17 (3H, m).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[C:5]1[CH:20]=[CH:19][C:8]([CH2:9][CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)[CH3:2].[H-].[Na+].[CH3:26][S:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1.CCOCC>CN(C=O)C>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([S:27][CH3:26])=[CH:29][CH:30]=2)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:19][CH:20]=1)[CH3:23]
Reactant: CSc1ccc(CCl)cc1
Reactant: CCOC(OCC)c1ccc(CC(C(=O)OC)C(=O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(OCC)c1ccc(CC(Cc2ccc(SC)cc2)(C(=O)OC)C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of the product from Step 1 (1.42 g, 4.4 mmol) in DMF (14 mL) at 0° C. was added NaH (131 mg, 80% in mineral oil). After 1 h. 4-(methylthio)benzyl chloride (0.64 mL, 4.4 mmol) was added and the mixture was stirred a further 2 h at 0° C. Following a standard aqueous/Et2O work-up, the crude was purified by flash column (1:20 EtOAc/toluene) to give a colorless oil (1.92 g).
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([OH:16])=O)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[N+:46]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH2:57])[CH3:56])=[CH:51][CH:50]=1)([O-:48])=[O:47]>CN(C=O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:23])[CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([NH:57][CH:55]([C:52]2[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:54][CH:53]=2)[CH3:56])=[O:16])=[CH:9][CH:10]=1)(=[NH:4])[NH2:3]
Reactant: C[C@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)c1ccc(NC(=O)C(C(=O)O)c2ccccc2)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(NC(=O)C(C(=O)Nc1ccc(C(=N)N)cc1)c1ccccc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
75 mg (0.235 mmol) of the sodium salt from example 2 were dissolved in 2.5 ml DMF. 85 mg (0.265 mmol) TOTU in 2.5 ml DMF were added and stirred for 30 min at rt. Then 34 μl (0.265 mmol) NEM and 53.7 mg (0.265 mmol) of (S)-1-(4-nitrophenyl)-ethylamine in 0.5 ml of DMF was added and the mixture stirred at rt overnight. After filtration, the filtrate was evaporated to dryness and purified by prep. RP-HPLC.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[OH:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(#N)C.CCCCCCC=CCCC>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([OH:32])=[CH:38][CH:37]=3)(=[O:40])=[O:41])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Agent: CCCC=CCCCCCC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(O)cc3)cc2)c(C)c1-c1ccccc1
Yield: 75.6 %

Procedure:
A mixture of phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22, 100 mg, 0.24 mmol), 4-hydroxybenzenesulfonamide (42 mg, 0.24 mmol), acetonitrile (3 mL) and 1,8-[5.4.0]-7-undecene (36 μL, 0.24 mmol) was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane, and washed with 1 M hydrochloric acid and sat. NaHCO3 aq. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 89 mg (74%) of the title compound as white solids: 1H-NMR [CDCl3/CD3OD(4:1)] δ 7.73-7.68 (2H, m), 7.48-7.23 (9H, m), 6.88-6.83 (2H, m), 3.47 (2H, t, J=6.7 Hz), 2.84 (2H, t, J=6.7 Hz), 2.33 (3H, s), 2.26 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1)([OH:23])=[O:22].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:31](=[S:32])[NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:21]([OH:23])=[O:22])=[CH:29][CH:28]=3)[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=C(O)c1ccc(N=C=S)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 4-carboxyphenyl isothiocyanate (0.183 g, 1.0 mmol) in tetrahydrofuran (10 mL) and was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The tetrahydrofuran was boiled off on the rotary evaporator (no vacuum) to give a solid. Ethyl acetate (5 mL) was added, and the mixture was allowed to stand overnight at room temperature. The insoluble material was collected by filtration and was a mixture. All material from the reaction mixture was taken up in tetrahydrofuran/ethyl acetate and more 4-carboxyphenyl isothiocyanate (0.020 g, 0.11 mmol) was added and the solvent was boiled off on the rotary evaporator. Ethyl acetate was added to the solid and the mixture allowed to stand overnight at room temperature. The insoluble material was collected by filtration (0.191 g), mp 201-203° C.