Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:20]1([C:26]([C:28]2[S:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:33][C:31]4[S:32][C:28]([C:26]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[O:27])=[CH:29][CH:30]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: O=Cc1ccc(C(=O)N2CCOCC2)s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(C(=O)N2CCOCC2)s1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
The mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (90 mg, 0.32 mmol), 5-(morpholine-4-carbonyl)-thiophene-2-carbaldehyde (82 mg, 0.36 mmol), and triethylamine (2 drops) in ethanol (3 mL) was heated at 90° C. oil bath for 2 hours, and cooled to room temperature. The solvent was evaporated and the residue was purified on a silica gel column eluting with methylene chloride-methanol (98:2 and 95:5) to provide pure 4-(3-chloro-4-fluoro-phenylamino)-5-{1-[5-(morpholine-4-carbonyl)-thiophen-2-yl]-methylidene}-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (41 mg, 28%). MS 486 [M++1].
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]1=[O:25].[C:26](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:26])[C:15]1=[O:25]
Reactant: O=C([O-])[O-]
Reactant: Nc1c2c(cc(F)c1-n1c(=O)cc(C(F)(F)F)[nH]c1=O)OCC(=O)N2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc3c(c2N)NC(=O)CO3)c1=O
Reaction time: 2 h
Yield: 79.4 %

Procedure:
3-[5-Amino-7-fluoro-2H-1,4-benzoxazine-3(4H)-on-6-yl]-6-trifluoromethyl-2,4-(1H, 3H)-pyrimidinedione (4.0 g) was dissolved in DMF (200 ml) containing potassium carbonate (5 g) and iodomethane (10 ml). After stirring for 2 hr, water (150 ml) and ethyl acetate (200 ml) were added. The organic phase was washed with water (50 ml×3) and brine (50 ml), dried over sodium sulfate. After filtration and evaporation, the residue was recrystallized from methylene chloride and hexane to afford the title compound (3.3 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([Cl:17])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[Cl:17][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=1)[C:6]([C:4]([OH:3])=[O:5])=[C:14]2[O:15][CH3:16]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1OC
Product: COc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccc(Cl)cc12

Procedure:
Using general procedure B, 5-chloro-3-methoxy-1H-indole-2-carboxylic acid ethyl ester (Lit. 9) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 364.1 ([M−H]−).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3](=O)[C:4](=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]2=[O:25])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[NH2:29]/[C:30](/[CH3:37])=[CH:31]\[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(O)C>[C:5]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([CH3:37])[NH:29][C:3]=1[C:2]([F:28])([F:1])[F:27])(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cc(=O)c2cccc(C=C(C(=O)c3ccccc3)C(=O)C(F)(F)F)c2o1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C(F)(F)F)=C(C(=O)c2ccccc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
A solution of 410 mg (1.06 mmol) of 4,4,4-trifluoro-2-[(2-methyl-4-oxo-4H-chromen-8-yl)-methylene]-1-phenylbutane-1,3-dione in 10 ml of 2-propanol is mixed with 137.3 mg (1.06 mmol) of ethyl 3-aminocrotonate and stirred under reflux for 12 h. After cooling, the reaction mixture is concentrated, and the residue is taken up in 5 ml of acetic acid and again stirred under reflux for 12 h. The reaction solution is concentrated and the residue is purified by preparative HPLC. 160.3 mg (30.3% of theory) of the title compound are obtained.
Reaction SMILES: ClC1C=C(C=CC=1Cl)CN(C)C(=O)C=C1C(=O)OC(C)(C)O1.C=O.NCCC(N)=O.[Cl:31][C:32]1[CH:33]=[C:34]([CH:57]=[CH:58][C:59]=1[Cl:60])[CH2:35][N:36]([CH3:56])[C:37]([C:39]1[CH2:43][N:42]([CH2:44][CH2:45][C:46]([NH:48]CCC(O)=O)=[O:47])[C:41](=[O:54])[C:40]=1[OH:55])=[O:38]>>[Cl:31][C:32]1[CH:33]=[C:34]([CH:57]=[CH:58][C:59]=1[Cl:60])[CH2:35][N:36]([CH3:56])[C:37]([C:39]1[CH2:43][N:42]([CH2:44][CH2:45][C:46](=[O:47])[NH2:48])[C:41](=[O:54])[C:40]=1[OH:55])=[O:38]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(=O)NCCC(=O)O)C1
Agent: C=O
Agent: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Agent: NCCC(N)=O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCC(N)=O)C1
Yield: 7 %

Procedure:
N-(3,4-Dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (Compound 37-A) was treated with paraformaldehyde and β-alaninamide as described in the preparation of Compound 37. The title compound was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber powder (0.0158 g, 7% yield). 1H NMR (300 MHz, CDCl3) δ: 2.68 (t, J=5.9 Hz, 2H), 3.02 (s, 3H), 3.79 (d, J=5.9 Hz, 2H), 4.29 (s, 2H), 4.58 (s, 2H), 6.23 (s, 1H), 6.59 (s, 1H), 7.09 (dd, J=8.4 Hz, J=10.3 Hz, 1H), 7.34 (d, J=1.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H). HRMS (M−H) calcd for C16H17N3Cl2O4: 384.05179. found: 384.0517.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)=[O:16])[CH:11]=2)[CH:6]=1)=[O:4].[CH:41]1([Mg]Br)[CH2:43][CH2:42]1>C1COCC1>[CH:41]1([C:15]([OH:16])([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:14]=[CH:13]3)[CH2:43][CH2:42]1
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C3CC3)ccc2c1

Procedure:
The similar reaction as described in Example 50-(i) was carried out by using N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (500 mg) and cyclopropyl-magnesium bromide in THF (1M; 4 mL) to give the titled compound (332 mg) as colorless powder.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:28])[C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=2)[C@H:9]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=2)[CH2:8]1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:17]=1)[C:13]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:38](=[O:45])[C:39]2[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=2)[CH2:8][C@H:9]1[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)=[O:28]
Reactant: Cc1ccc(C[C@@H]2CN(CCCN)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: O=C(O)c1cccnc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C[C@@H]2CN(CCCNC(=O)c3cccnc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
To a stirred mixture of (2R)-4-(3-aminopropyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-piperazine dihydrochloride (160 mg), nicotinic acid (33 mg) and triethylamine (0.17 ml) in dichloromethane (2 ml) was added 2-chloro-1-methylpyridinium iodide (78 mg) at room temperature. After stirring for 1.5 hours, the reaction mixture was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (30 ml) and water (10 ml). The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on a silica gel with dichloromethane-methanol (40:1) as eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[3-(nicotinoylamino)propyl]-piperazine (70 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:12][CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@:9]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:12][CH:13]=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]1(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1CCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@H]1CC=O
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a solution of (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-hydroxyethyl)cyclopropanecarboxylate (8.65 g, 23.2 mmol) in dichloromethane (116 ml) at 25° C. was added Dess-Martin Periodinane (13.8 g, 32.4 mmol). The mixture was stirred for 3 h and quenched with 1 N sodium thiosulfate (70 mL) and aqueous saturated sodium bicarbonate solution (30 mL), and stirred for 1 h. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. This material was purified by flash chromatography on silica gel (eluted with 25% ethyl acetate/hexane) to yield (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-oxoethyl)cyclopropanecarboxylate (7.05 g, 82% yield) as an oil. MS (ESI): m/z=394.1 [M+Na]. To (1R,2S)-ethyl 1-(bis(tert-butoxycarbonyl)amino)-2-(2-oxoethyl)cyclopropanecarboxylate (7.05 g, 19.0 mmol) in tetrahydrofuran (60 mL) at −78° C. was added but-3-enylmagnesium bromide (45.6 mL, 22.78 mmol) and the reaction mixture was stirred for 30 min. The mixture was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The residual oil was purified via flash chromatography on silica gel (25% hexane/ethyl acetate) to provide the title compound (2.75 g, 34%) as an oil, along with recovered starting material (2.89 g, 41%). MS (ESI): m/z=450.1 [M+Na].
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:9][C@H:8]1[C:13]([O:15][CH3:16])=[O:14])=[O:6])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-hydroxypyrrolidine (210.2 g) and triethylamine (150.2 ml) in dichloromethane (2 l) was added dropwise methanesulfonyl chloride (70.7 ml) at 0° C. After stirring for 1 hour at 0° C., the reaction mixture was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give (2S,4R)-1-allyloxycarbonyl-2-methoxycarbonyl-4-methanesulfonyloxypyrrolidine (281.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]=[C:15]=[S:16])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH3:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15]([NH2:17])=[S:16])=[CH:6][CH:7]=1
Reactant: N
Reactant: S=C=Nc1ccccc1-c1ccc(Cl)cc1
Solvent: CCO
Product: NC(=S)Nc1ccccc1-c1ccc(Cl)cc1

Procedure:
Reaction of 4'-chloro-2-biphenylylisothiocyanate (7.6 g) with ethanol (100 ml) with 25% aqueous ammonia solution (15 ml) for 18 hours at ambient temperature yielded N-(4'-chloro-2-biphenylyl)thiourea (m.p. 175°-177° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:16]Br)=[N:14][N:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12](=[O:24])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1.[C-:25]#[N:26].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:16][C:25]#[N:26])=[N:14][N:13]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:12](=[O:24])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Cn1c2cccc(Br)c2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cn1c2cccc(Br)c2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Yield: 99.3 %

Procedure:
A solution of 6.4 g (14.3 mmol) of 9-bromo-1-(bromomethyl)-5-methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 3.6 g (73 mmol) of sodium cyanide and of 0.57 g (1 mmol) of tetrabutylammonium bromide in a mixture of 170 ml of dichloromethane and of 85 ml of water is heated at reflux for 3 h with mechanical stirring. Separation is carried out by settling and the reaction mixture is extracted with dichloromethane. The organic phase is washed with water and dried over sodium sulphate and the solvent is evaporated under reduced pressure. 5.6 g (14.2 mmol) of product are obtained, which product is used as is in the following stage.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=3)[N:12]=[C:11]([C:23]#[N:24])[CH:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([F:22])([F:20])[F:21])[CH:17]=2)[N:12]=[C:11]([C:23]#[N:24])[CH:10]=1
Reactant: COc1ccc(COc2cc(C#N)nc3ccc(C(F)(F)F)cc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(O)c2cc(C(F)(F)F)ccc2n1

Procedure:
A solution of 4-((4-methoxybenzyl)oxy)-6-(trifluoromethyl)quinoline-2-carbonitrile (5 g, 14 mmol) from above step C, in 15 mL DCM and 45 mL TFA was stirred for 2 h. Solvent was removed under vacuum and the residue was evaporated form toluene twice. The residue was dried under high vacuum. The resulting yellow solid was triturated with hot toluene, filtered and washed with ether to provide the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:34]1([CH2:37][N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:36][CH2:35]1>>[CH:34]1([CH2:37][N:38]2[CH2:43][CH2:42][N:41]([C:1](=[NH:2])[C:3]3[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]4[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]5[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=5)(=[O:20])=[O:19])=[CH:14][CH:13]=4)[CH:6]=[CH:7][CH:8]=3)[CH2:40][CH2:39]2)[CH2:36][CH2:35]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCN(CC2CC2)CC1
Yield: 57 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2.2 equivalent of 1-(cyclopropylmethyl)piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[O:10]CC)=[CH:4][CH:3]=1.[OH:14][CH:15]([C:21]([CH3:23])=[CH2:22])[C:16]([O:18]CC)=O.C(N(CCCC)CCCC)CCC.Cl>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:18])[C:15](=[C:21]([CH3:22])[CH3:23])[O:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Nc1ccc(C)cc1
Reactant: C=C(C)C(O)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)=C1OC(=O)N(c2ccc(C)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
Ethyl N-(4-methylphenyl)carbamate (2.87 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (3.90 g, 30 mmol), tetrabutylammonium chloride (139 mg, 0.5 mmol) and tributylamine (92.7 mg, 0.5 mmol) were introduced into a flask (25 cc) equipped with a distillation unit, and the reaction was conducted at 200° C. for 8 hours. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and then the reaction solution was washed with water (20 mL), then 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. To the resulting oily crude product, methanol (3.5 mL) acidified with hydrochloric acid was added to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, then washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-methylphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.07 g, yield 46.1%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[CH3:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:19]=1[CH2:20]Cl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(#N)C>[CH3:15][C:13]1[N:14]=[C:3]2[C:2]([NH:1][CH2:20][C:19]3[C:22]([CH3:26])=[CH:23][CH:24]=[CH:25][C:18]=3[CH3:17])=[CH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]2[C:12]=1[CH3:16]
Reactant: Cc1cccc(C)c1CCl
Reactant: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(NCc2c(C)cccc2C)c2nc(C)c(C)n2c1
Yield: 18.9 %

Procedure:
Methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (0.8 g, 3.6 mmol), 2,6-dimethylbenzylchloride (0.57 g, 3.7 mmol), sodium carbonate (1.0 g, 9.4 mmol) and a catalytic amount of potassium iodide were added to acetonitrile (10 ml) and were refluxed for 20 h. Following filtration, the salts were washed with methylene chloride and the solvents were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride: ethyl acetate (75:25) as eluent. The yellow residue was treated with hexane to give 0.23 g (19%) of the title product.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:25])=[C:5]([C@@:9]([OH:24])([C@@H:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:49][CH:50]1[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51]1)[CH2:35][NH:36][C:37](=O)[O:38]C1C=CC([N+]([O-])=O)=CC=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CCN(C(C)C)C(C)C>CC#N.C(Cl)Cl.CCOCC>[C:26]([O:30][C:31]([NH:33][C@@H:34]([CH2:49][CH:50]1[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55]1)[CH2:35][NH:36][C:37]([N:20]1[CH2:21][CH2:22][CH2:23][C@@H:18]([C@@:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[C:4]=2[F:25])([OH:24])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:17])[O:15][CH3:16])[CH2:19]1)=[O:38])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(=O)Oc1ccc([N+](=O)[O-])cc1)CC1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)NC[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
To a stirred suspension of the HCl salt of methyl (S)-4-(3-chloro-2-fluorophenyl)-4-hydroxy-4-((R)-piperidin-3-yl)butylcarbamate (31.6 mg, 0.08 mmol) and (S)-4-nitrophenyl 2-(t-butoxycarbonylamino)-3-cyclohexylpropylcarbamate (45 mg, 0.105 mmol) in MeCN (1 mL) and CH2Cl2 (1 mL) was added DIEA (80 μL, 0.45 mmol). The mixture was stirred at rt for 3 d, diluted with ether (90 mL), washed with 5% aq HCl (20 mL), IM aq NaOH (20 mL) and brine (20 mL), and dried over MgSO4. Removal of the solvent left a white solid (61 mg) which was applied to a 2-g silica SPE cartridge. The cartridge was eluted sequentially with 0, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford five fractions. Fractions 4 and 5 were pooled and concentrated to afford methyl (S)-4-((R)-1-((S)-2-(t-butoxycarbonylamino)-3-cyclohexylpropylcarbamoyl)piperidin-3-yl)-4-(3-chloro-2-fluorophenyl)-4-hydroxybutylcarbamate (35 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH:28]=O)=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH2:28][N:36]6[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]6)=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:34][CH:35]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C=O)ccc3c12
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(CN4CCCCC4)ccc3c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 40.9 %

Procedure:
Step 2 A suspension of 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-formyl-9H-carbazole-1-carboxamide (30 mg, 0.064 mmol) in THF (3 mL) was treated with piperidine (16.46 mg, 0.193 mmol) and sodium triacetoxyborohydride (34.1 mg, 0.161 mmol). The mixture was stirred at rt for 3.5 h, the was treated again with additional piperidine (16.5 mg, 0.193 mmol) and sodium triacetoxyborohydride (20 mg). After stirring overnight, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was purified by preparative HPLC to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(piperidin-1-ylmethyl)-9H-carbazole-1-carboxamide (14 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 8.06 (2 H, dd, J=8.7, 5.4 Hz), 7.98 (1 H, d, J=7.8 Hz), 7.63 (1 H, s), 7.52 (1 H, d, J=7.3 Hz), 7.44 (1 H, t, J=7.8 Hz), 7.18-7.31 (3 H, m), 7.07 (2 H, d, J=7.5 Hz), 6.96-7.02 (1 H, m), 3.96 (2 H, s), 2.72-2.88 (4 H, m), 1.99 (3 H, s), 1.63-1.75 (4 H, m), 1.48-1.60 (2 H, m). Mass spectrum m/z 535.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[S:17][C:16]([C:18]3([O:24][CH3:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[OH:5].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][C:9]([S:12][C:13]2[S:17][C:16]([C:18]3([O:24][CH3:25])[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: COC1(c2ccc(Sc3ccc(C(O)c4ccc(F)cc4F)cc3)s2)CCOCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COC1(c2ccc(Sc3ccc(C(=O)c4ccc(F)cc4F)cc3)s2)CCOCC1
Yield: 71 %

Procedure:
Using the procedure described in Example 18, 4-[5-(4-(2,4-difluoro-alpha-hydroxybenzyl)phenylthio)thien-2-yl]-4-methoxytetrahydropyran was reacted with pyridinium chlorochromate to give 4-[5-(4-(2,4-difluorobenzoyl)phenylthio)thien-2-yl]-4-methoxytetrahydropyran in 71% yield, as an oil.