Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=1.[NH2:38][C:39]1[CH:54]=[CH:53][C:42]2[N:43]([CH2:51][CH3:52])[CH2:44][C:45]([CH2:49][OH:50])([OH:48])[CH2:46][O:47][C:41]=2[CH:40]=1>C(O)(C)C>[Cl:37][C:20]1[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])=[N:22][C:17]([NH:38][C:39]2[CH:54]=[CH:53][C:42]3[N:43]([CH2:51][CH3:52])[CH2:44][C:45]([OH:48])([CH2:49][OH:50])[CH2:46][O:47][C:41]=3[CH:40]=2)=[N:18][CH:19]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CC(O)(CO)COc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCC(O)(CO)CN3CC)ncc1Cl

Procedure:
10-Camphorsulfonic acid (107 mg, 0.462 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide (142 mg, 0.420 mmol), and 3-Amino-9-ethyl-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-ol (0.100 g, 0.420 mmol) in Isopropyl alcohol (3.0 mL) and the mixture was irradiated in a CEM microwave (120° C., 40 min). The reaction mixture was then purified by HPLC and lyophilized to afford 2-[5-Chloro-2-(9-ethyl-7-hydroxy-7-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide as a yellow lyophilate (2 mg, 1%). LCMS: 541.31 (M+H); HNMR (CDCl3): 9.33 (s, 1H), 8.02 (s, 1H), 7.46 (d, J=5.32 Hz, 4H), 7.33 (s, 1H), 6.97 (s, 1H), 6.65 (d, J=7.80 Hz, 1H), 4.05 (m, 4H), 3.87 (s, 2H), 3.51 (s, 2H), 3.13 (s, 2H), 1.12 (t, J=7.04 Hz, 3H);
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([NH2:16])[CH2:14][NH2:15].C(O)C>O>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:15][CH2:14][CH2:13][NH2:16])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: NCCN
Solvent: O
Solvent: CCO
Product: NCCNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]

Procedure:
0.13 mole (30.6 g) of 2,4,5-trichloronitrobenzene is added to a solution of 78 g of ethylenediamine in 100 ml of 96° ethanol and 117 ml of water. After heating under reflux for 1 h 30 min, the reaction mixture is cooled. After dilution with iced water, the expected product precipitates. It melts as 84° C.-87° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[O:12][CH:13]=2)O1.Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[N:21]1[C:20]2[NH:24][CH:25]=[CH:26][C:19]=2[C:18]([C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[O:12][CH:13]=2)=[N:23][CH:22]=1
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2ncnc3[nH]ccc23)co1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
1 g [4.5 mMols] of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furan-2-carbaldehyde, 550 mg [3.6 mMols]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine and 1.52 g [6.7 mMols] of tripotassium phosphate were placed in 20 mL DMF and 10 mL water and purged with nitrogen gas while stirring for 10 minutes at ambient temperature. To this stirring suspension, 400 mg, 0.45 mMols] of tetrakistriphenylphosphine palladium (0) was added in one portion, and reaction vessel was placed in a preheated bath at 110° C. The reaction was stirred and heated under a nitrogen atmosphere for 30 minutes (deemed complete by analytical liquid chromatography). The reaction mixture was cooled and suction filtered to remove the ligand present as a precipitate, which was washed with a little DMF/H2O 2:1. The combined filtrates were reduced in volume to one quarter of the original under reduced pressure and diluted slowly with water with stirring. The resulting fine precipitate was centrifuged down and the pellet was washed with more water, re-centrifuged and transferred to a RB with acetonitrile. This solvent was reduced to dryness under reduced pressure. The material, 670 mg (yield 87%) of a light beige powder was carried on without further purification. LC/ms m+1=214.
Reaction SMILES: [OH:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].N1C=CN=C1.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18].O>CN(C=O)C>[Si:21]([O:1][C@H:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:17]([CH3:20])([CH3:19])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCC[C@@H](C)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCC[C@@H](C)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
To a solution of (R)-ethyl 5-hydroxyhexanoate (5 g, 31.2 mmol) in DMF (100 mL) at 0° C. was added imidazole (3.19 g, 46.8 mmol) followed by tert-butylchlorodiphenylsilane (12.00 mL, 46.8 mmol) and the resulting mixture was stirred at room temp for 16 h. Water (30 mL) was then added and the mixture was extracted with ether (2×100 mL). Ether layer was then washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. The residue was purified via Biotage (0-10% EtOAc/hexane) to afford (R)-ethyl 5-((tert-butyldiphenylsilyl)oxy)hexanoate (10 g, 25.09 mmol, 80% yield) as clear viscous liquid. 1H NMR (500 MHz, CDCl3) δ 7.73-7.68 (m, 4H), 7.48-7.36 (m, 6H), 4.13 (q, J=7.2 Hz, 2H), 3.96-3.76 (m, 1H), 2.31-2.16 (m, 2H), 1.72-1.62 (m, 2H), 1.58-1.40 (m, 2H), 1.27 (t, J=7.1 Hz, 3H), 1.12-1.05 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([O:25]C)=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[O:27][CH3:28])=[O:10].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=2)[CH2:14][C@H:13]1[O:27][CH3:28])=[O:10]
Reactant: COC(=O)c1cnc(N2CC[C@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@H](OC)C2)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 50 °C

Procedure:
Cis(±)methyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylate (Example 1; 200 mg) was dissolved in THF (50 ml). 2N LiOH (100 ml) was added and the mixture was heated at 50° C. for 18 h. The reaction mixture was cooled to ambient and acidified with 20% aqueous citric acid. The aqueous phase was extracted with EtOAc and the organic phase was washed with water, brine, dried over Na2SO4. The organic phase was concentrated in vacuo and triturated with diethyl ether to give the title compound as an off white solid. (164 mg). MS (ES) MH+: 433, 431 for C16H18Cl2N4O4S; NMR: 1.87 (m, 2H), 2.28 (s, 3H), 3.32 (m, 6H), 3.63 (s, 1H), 3.87 (m, 1H), 4.45 (m, 2H), 7.04 (d, 1H), 7.90 (s, 1H), 11.97 (s, 1H), 12.30 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:3]=1
Reactant: NCCN1CCOCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(NCCN2CCOCC2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with N-(2-aminoethyl)morpholine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[NH2:27].Cl>O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:27][CH:23]2[CH2:24][CH2:25][CH2:26][CH:22]2[CH3:21])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC1CCCC1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCCC2C)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of 9.32 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 30 ml of abs. DMF was added 16.47 g of potassium carbonate, followed by 5.00 g of 2-methyl-cyclopentylamine. After 16 h at rt, the mixture was poured into water, the pH was adjusted to 5 by the addition of 2 M aqueous hydrochloric acid, and the reaction mixture was extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 12.74 g (100%) of 4-(2-Methyl-cyclopentylamino)-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [Cl-].[CH2:2]([N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[S:12]([O:16]C)([O:14]C)=[O:13]>>[CH3:2][S:12]([O-:16])(=[O:14])=[O:13].[CH2:2]([N+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]
Reactant: COS(=O)OC
Agent: CCCC[n+]1ccccc1
Agent: [Cl-]
Product: CS(=O)(=O)[O-]
Temperature: 112.5 °C
Reaction time: 72 h

Procedure:
A mixture of 11.88 g (69.2 mmol) of 1-butylpyridinium chloride and 13.69 g (124.3 mmol) of dimethyl sulfite is stirred at 110-115° C. (temperature of the oil bath) for 72 hours under an inert-gas atmosphere (nitrogen) in a sealed reaction vessel with pressure valve for 1-1.5 bar above atmospheric pressure. The end of the reaction is determined by NMR measurement. The product is pumped off over the course of 5 hours in vacuo at 13.3 Pa and 115° C. (temperature of the oil bath), giving 15.51 g of 1-butylpyridinium methanesulfonate as a solid. The melting point is 91-92° C. The yield is 96.9%. The residual chloride content is less than 5 ppm. The product is investigated by means of NMR spectroscopy.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([OH:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([O:21][CH2:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: ClCc1ccncc1
Agent: Cl
Product: Cc1c(C)c2c(c(C)c1OCc1ccncc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 52 %

Procedure:
Using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran-5-ol and 4-chloromethylpyridine hydrochloride, the title compound was obtained in the same manner as in Example 1. This was oily.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:12][CH2:11][N:10]2[C:13](=[O:30])[C:14]3[C:19]4[CH2:20][CH2:21][C:22]([CH:28]=[O:29])=[C:23]([S:24][CH2:25][CH2:26][CH3:27])[C:18]=4[S:17][C:15]=3[N:16]=[C:9]2[CH2:8][CH2:7]1)=[O:5])C.[OH-].[K+].O.Cl>CO>[CH3:1][O:3][C:4]([CH:6]1[CH2:12][CH2:11][N:10]2[C:13](=[O:30])[C:14]3[C:19]4[CH2:20][CH2:21][C:22]([CH:28]=[O:29])=[C:23]([S:24][CH2:25][CH2:26][CH3:27])[C:18]=4[S:17][C:15]=3[N:16]=[C:9]2[CH2:8][CH2:7]1)=[O:5]
Reactant: CCCSC1=C(C=O)CCc2c1sc1nc3n(c(=O)c21)CCC(C(=O)OCC)CC3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCSC1=C(C=O)CCc2c1sc1nc3n(c(=O)c21)CCC(C(=O)OC)CC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 22 80.37 mmol) was dissolved into MeOH (10 ml), and KOH (0.98 mmol) in MeOH (5 ml) was added. The reaction mixture was stirred for 2 hours in room temperature. The reaction mixture was poured into water, acidified with HCl and extracted with CH2Cl2. Organic layer was washed with brine and dried with Na2SO4. After filtration the solvent was evaporated. Purification by flash chromatography using CH2Cl2-EtOAc 9:1 as an eluent afforded compound 23 as a major product and compound 24 as a minor product.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=1)=[O:6])[CH3:3].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:32][CH2:33][CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:36][CH2:35]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:2]([O:4][C:5]([C:7]1[CH2:8][N:9]([CH2:32][CH2:33][CH:34]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[O:36][CH2:35]2)[CH2:10][CH2:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1=CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3C2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CCCN(CCC2COc3ccccc3C2)C1
Reaction time: 16 h
Yield: 52.3 %

Procedure:
First 2.1 g (11 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride and then 4.53 g (35 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.32 g (10 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 1.65 g (52.3%) of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether and melts at 177°-178°.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH:8]1([N:11]2[C:15]([C:16]3[CH:17]=[C:18]([CH:22]4[CH2:31][C:30]([CH3:33])([CH3:32])[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:34](O)=[O:35])[CH:28]=5)[NH:23]4)[CH:19]=[CH:20][CH:21]=3)=[N:14][N:13]=[N:12]2)[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:8]1([N:11]2[C:15]([C:16]3[CH:17]=[C:18]([CH:22]4[CH2:31][C:30]([CH3:32])([CH3:33])[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:34]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:35])[CH:28]=5)[NH:23]4)[CH:19]=[CH:20][CH:21]=3)=[N:14][N:13]=[N:12]2)[CH2:10][CH2:9]1
Reactant: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)O)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535.0 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (1.3 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A43. A solution of 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (544.6 mg, 1.4 mmol) and 1,1′-carbonyldiimidazole (442.0 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B43. Solution B43 was added to Solution A43 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-{2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-methanesulfonamide (195.7 mg, 30%) as a white solid: MS (ESI) M+1=467.2.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>O1CCOCC1>[CH3:33][N:34]([CH3:38])[C:35]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:23])[CH2:15][CH2:14]1)=[O:36]
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)C(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea (0.8 mmol), prepared as described in general procedure (G), steps 1-3, and 1.2 equivalents of DIPEA in 10 mL dioxane was added dimethylcarbamoyl chloride (1.2 equivalents) in 1 ml dioxane. The reaction was stirred overnight at room temperature, concentrated in vacuo and purified by flash chromtography to give the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:15](OCC)=[O:16].Cl>CN(C=O)C>[CH:15]([CH:7]([CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:16]
Reactant: CCOC(=O)CCC1CCCC1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
40.7 g of ethyl 3-cyclopentylpropionate are placed in 400 ml of DMF at from 0° to 5° C., 14.4 g of sodium hydride (80% in oil) are added. After dropwise addition of 200 ml of ethyl formate, the mixture is stirred at 25° C. for 24 h. The mixture is stirred into 1.6 l of 10% HCl, extracted with 800 ml of methylene chloride and distilled. 19.7 g (41%) are obtained of ethyl 2-formyl-3-cyclopentylpropionate of boiling point 117° C./12 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(OC(N=NC(OCC)=O)=O)C>C1(C)C=CC=CC=1.C1COCC1>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
Under nitrogen atmosphere, 3-cyano-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound A6, 85 mg, 0.28 mmol) and triphenylphosphine (150 mg, 2 eq.) were added with THF (2 ml), and then further added dropwise with 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, 2 eq.) and 2.19 N toluene solution of diethyl azodicarboxylic acid (0.26 mL, 2 eq.). The resultant was stirred at room temperature for 12 hr under nitrogen atmosphere. The residues obtained after concentrating the reaction solution under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (white powder, 120 mg).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[N:18]=3)=[CH:8][CH:7]=2)[CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:24](C)=O.[Na+].C=O.C(O)(=O)C>CO>[Br:19][C:17]1[N:18]=[C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH:4]3[CH2:5][N:2]([CH3:24])[CH2:3]3)=[CH:11][CH:10]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CNC3)cc2)c1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(c2ccc(Nc3nc(Br)cn(C)c3=O)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 119.3 %

Procedure:
A mixture of 298c (100 mg, 0.24 mmol), NaBH(OAc)3 (100 mg, 0.48 mmol), HCHO (10 mL) and acetic acid (1 mL) in methanol (15 mL) was stirred at room temperature for 4 h. The solvent was evaporated in vacuo and the residue was neutralized with NaHCO3 solution until pH 8 was reached. The mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give 298d (100 mg), which was used for the next step without further purification. MS: [M+H]+ 349.
Reaction SMILES: [Mg].[CH3:2][C:3]1[N:8]=[C:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH3:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)([OH:21])[CH2:19][CH3:18])=[CH:13][CH:12]=2)[N:8]=1
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: Cc1cccc(COc2ccc(Br)cc2)n1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(F)cc1)c1ccc(OCc2cccc(C)n2)cc1
Temperature: 25 °C

Procedure:
To a Gringard reactant prepared from 2.2 g. of magnesium turnings and 25 g. of 4-[(6-methylpyrid-2-yl)-methoxy]-bromobenzene in 120 ml. of dry tetrahydrofurane a solution of 9.1 g. of 4-fluoropropiophenone in 45 ml. of tetrahydrofurane is added dropwise at 0° C. The reaction mixture is stirred at room temperature for two additional hours, and is then decomposed with a saturated aqueous ammonium chloride solution, under cooling. The aqueous phase is extracted with tetrahydrofurane. The tetrahydrofurane phase is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Crystallization of the crude product from a mixture of ethyl acetate and n-hexane yields 15.2 g. of the title compound, melting at 103° to 104° C.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH3:8][C:9]([CH3:11])=O>C1COCC1>[C:9](=[N:7][S:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([CH3:11])[CH3:8]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
To a solution of 2-Methyl-2-propanesulfinamide (1.47 g) and acetone (0.98 ml) in THF (24 ml) chilled to 0° C. was added Ti(OEt)4 (5.36 ml) dropwise over the course of 15 minutes. After being stirred at room temperature for 3 days, the reaction mixture was quenched by the rapid addition into ice cooled saturated sodium bicarbonate solution. The suspension was filtered through glass fiber filter paper, washing with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate solution and brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-60% ethyl acetate in hexanes) gave the product (0.923 g, 47%). 400 M Hz 1H-NMR (CDCl3) δ: 2.34 (s, 3H), 2.18 (s, 3H), 1.23 (s, 9H).