Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:15][O:16][CH2:17]Cl.O>CN(C=O)C>[CH3:15][O:16][CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(I)cc1
Yield: 88 %

Procedure:
Paraiodophenol (25 g) was dissolved in DMF (100 ml), followed by the addition of potassium t-butoxide (25 g) and methoxymethyl chloride (13 ml), and the mixture was reacted at 60° C. overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and evaporated. The resulting residue was subjected to a silica gel short column, to give 4-methoxymethoxy-1-iodobenzene as an oil (26.5 g, yield; 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][NH:21][CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][N:21]([C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: CCNCc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1
Reactant: O=C(Cl)C1CC1
Product: CCN(Cc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-5′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:5]2=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:35](Cl)([Cl:37])=[O:36].C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:14]([CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:13][N:12]([C:35]([Cl:37])=[O:36])[CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 8, rac-(2′R,3′S,4′S)-6-chloro-2′-(3-chloro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 16 (0.3 g, 0.74 mmol) was reacted with a toluene solution (Aldrich, 20%) of phosgene (0.7 mL, 1.3 mmol) and saturated aqueous NaHCO3 solution (5 mL) in dichloromethane (5 mL) to give rac-(2′R,3′S,4′S)-6-chloro-2′-(3-chloro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride as a yellow oil (Yield, 0.34 g, 100%), which was used in the next step without further purification.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=3)[N:10]=2)[CH:5]([CH2:22][CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4]1)=[O:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-:53]>C1COCC1>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=3)[N:10]=2)[CH:5]([CH2:22][CH2:23][CH2:24][F:53])[CH2:4]1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CN(C=O)CCN2c2ccc3cc([N+](=O)[O-])ccc3n2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=CN1CCN(c2ccc3cc([N+](=O)[O-])ccc3n2)C(CCCF)C1
Temperature: 55 °C

Procedure:
A solution of 3-(4-formyl-1-(6-nitroquinolin-2-yl)piperazin-2-yl)propyl-4-methylbenzene-sulfonate 30 (0.056 g, 0.11 mmol) in dry THF (0.30 mL) was treated with a solution of TBAF (0.16 mL, 1 M in THF, 0.16 mmol) to give a dark orange solution. The reaction mixture was heated at 55° C. for 2 h, and then was concentrated in vacuo and diluted with CHCl3. The crude material was purified by column chromatography to give N-Formyl-3-(3-fluoropropyl)-4-(6-nitroquinolin-2-yl)piperazine, 31 as a yellow foam (0.025 g, 64%). 1H NMR (CDCl3, 400 MHz) δ1.60-2.00 (m, 4H), 2.90 (dt, J=3.6 and 12.3 Hz, 0.5H), 3.00 (dd, J=4.2 and 13.3 Hz, 0.5H), 3.20-3.40 (2m, 2H), 3.44-3.62 (m, 1.5H), 3.72 (bd, 0.5H), 4.32-4.60 (m, 3H), 4.83 (bs, 0.5H), 5.07 (bs, 0.5H), 7.07 (dd, J=3.2 and 9.4 Hz, 1H), 7.69 (m, 1H), 8.03 (d, J=9.1 Hz, 1H), 8.10 (s, 0.5H), 8.25 (s, 0.5H), 8.32 (dd, J=2.6 and 9.1 Hz, 1H), 8.56 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH2:12]([NH2:15])[CH:13]=[CH2:14]>O>[CH2:12]([NH:15][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12)[CH:13]=[CH2:14]
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: C=CCN
Solvent: O
Product: C=CCNc1cc(C)nc2cn[nH]c12
Yield: 88.5 %

Procedure:
A mixture of 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D4) (1.0 g, 0.006 mole) and allylamine (60 g) in water (100 ml) was heated under reflux for 12 days. On cooling the reaction mixture was evaporated to dryness, basified to pH8 with 10% sodium carbonate solution and the resulting solid filtered off. Recrystallisation from chloroform/pentane gave the product as white solid (1.0 g). m.p. 172°-174° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([C:22]3[S:23][CH:24]=[C:25]4[C:29]=3[NH:28][C:27](=[O:30])[N:26]4C(OC(C)(C)C)=O)=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([C:38]1[S:39][CH:40]=[C:41]3[C:45]=1[NH:44][C:43](=[O:46])[N:42]3C(OC(C)(C)C)=O)[CH:14]=2.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:8][N:9]1[C:21]2[CH:20]=[CH:19][C:18]([C:22]3[S:23][CH:24]=[C:25]4[C:29]=3[NH:28][C:27](=[O:30])[NH:26]4)=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[C:13]([C:38]1[S:39][CH:40]=[C:41]3[C:45]=1[NH:44][C:43](=[O:46])[NH:42]3)[CH:14]=2
Reactant: Cn1c2ccc(-c3scc4c3[nH]c(=O)n4C(=O)OC(C)(C)C)cc2c2cc(-c3scc4c3[nH]c(=O)n4C(=O)OC(C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1c2ccc(-c3scc4[nH]c(=O)[nH]c34)cc2c2cc(-c3scc4[nH]c(=O)[nH]c34)ccc21
Reaction time: 3 h

Procedure:
Trifluoroacetic acid in an amount of 40 equivalents was added to the obtained tert-butyl 4-[9-methyl-6-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)-9H-carbazol-3-yl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate and a reaction was carried out at 25° C. for 3 hours. The resulting reaction liquid was dropped slowly to a saturated aqueous sodium carbonate solution to neutralize, thereby stopping the reaction. Ethyl acetate was added to the reaction liquid and stirred, and then an organic layer was taken and the solvent was distilled off. The residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 4-[9-methyl-6-(2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)-9H-carbazol-3-yl]-2,3-dihydro-1H-thieno[3,4-d]imidazol-2-one was obtained. The yield based on the charged tert-butyl 4-[9-methyl-6-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)-9H-carbazol 3-yl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxy late was 90%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=[O:28])[C:22](=[O:27])[C:23]=4OCC)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][NH2:30].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]4[C:21](=[O:28])[C:22](=[O:27])[C:23]=4[NH:30][CH3:29])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Solvent: O
Solvent: CCO
Product: CNc1c(Nc2ccc3ncnc(Nc4cccc(Br)c4)c3c2)c(=O)c1=O
Temperature: 25 °C

Procedure:
A mixture of 0.8 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1,2-dione, 15 mL of 33 % methylamine, 5 mL of water, and 5 mL of ethanol was refluxed for 5 hr. The mixture was cooled to room temperature and the solid was collected and washed with ethanol and ether giving 0.45 g of 3-[4-(3-Bromo-phenylamino)-quinazolin-6-ylamino]-4-methylamino-cyclobut-3-ene-1,2-dione as a yellow powder: mass spectrum (m/e): M+H 426.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:10]=1.[CH3:37][NH:38][CH3:39].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([CH3:28])[C:25]([N:38]([CH3:39])[CH3:37])=[O:26])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])[N:10]=1
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)C(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of 2-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-propionic acid, (100 mg, 0.20 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 547 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(S(O)(=O)=O)(F)(F)F.C1C(=O)N([Br:26])C(=O)C1>CC#N>[Br:26][C:7]1[C:8]([OH:10])=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(Br)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzonitrile (10 g, 65.1 mmol) in CH3CN (200 mL) was added CF3SO3H (6.33 g, 71.6 mmol) and NBS (16.2 g, 94.1 mmol) at −30° C. After being stirred for 18 hours at room temperature, the mixture was quenched with aq. saturated NaHSO4 solution and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the product 37 (10.5 g, 66%) as a white solid.
Reaction SMILES: [OH-:1].[Na+].O.CS([C:7]1[N:12]=[CH:11][C:10]2=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]2[N:8]=1)=O>C(O)(=O)C>[OH:1][C:7]1[N:12]=[CH:11][C:10]2=[CH:13][CH:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[N:9]2[N:8]=1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(c1ccccc1-c1ccc2cnc(O)nn12)S(C)(=O)=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Into a 8-dram vial, 19.10 M of Sodium hydroxide in Water (7.88 mL, 1.50E2 mmol) and Water (7.88 mL, 438 mmol) water were added. The mixture was heated at 100° C. N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (2.00 g, 5.49 mmol) was added portion wise over 10 minutes. The reaction mixture was heated at 120° C. for 60 minutes. HPLC suggested no SM. The reaction was cooled to room temperature. Glacial acetic acid was added to adjust pH to 4. The mixture was stirred at room temperature for 30 minutes. The solid was filtered, washed with water and subsequently with Et2O. The resulting solid was dried under vacuum overnight to give N-[2-(2-Hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a yellow solid (1.60 g, 92%).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([CH2:38][OH:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:24][C:25]1[N:29]=[CH:28][NH:27][CH:26]=1)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.Br.[N+:41]([C:44]1[C:45]([S:50][S:51][CH2:52][CH2:53][C:54]([OH:56])=O)=[N:46][CH:47]=[CH:48][CH:49]=1)([O-:43])=[O:42].ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)C.C(O)(=O)C>[N+:41]([C:44]1[C:45]([S:50][S:51][CH2:52][CH2:53][C:54]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]([C:30]([NH:32][C@H:33]([CH2:38][OH:39])[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:31])[CH2:24][C:25]2[N:29]=[CH:28][NH:27][CH:26]=2)=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:56])=[N:46][CH:47]=[CH:48][CH:49]=1)([O-:43])=[O:42]
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: O=C(O)CCSSc1ncccc1[N+](=O)[O-]
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CCSSc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.16 g. (0.3 mmole) of N-benzyloxycarbonyl-L-phenylalanyl-L-histidyl-L-leucinol were added 3 ml. of a 25% w/v glacial acetic acid solution of hydrogen bromide. The mixture was stirred at room temperature for 30 minutes, and then anhydrous diethyl ether was added thereto. The precipitate thus formed was separated by filtration and dissolved in 5 ml. of dimethylformamide. The solution was cooled with ice, and then there were added 30 mg. of N-methylmorpholine for neutralization. To the neutralized solution were added an active ester prepared from 86 mg. (0.33 mmole) of 3-(3-nitro-2-pyridyldithio)propionic acid, 39 mg. (0.33 mmole) of 1-hydroxybenztriazole and 74 mg. (0.36 mmole) of DCC. The mixture was stirred for 1 hour whilst cooling with ice and then overnight at room temperature, after which it was treated in a conventional manner to give a yellow powder, which was purified by silica gel column chromatography (eluent: chloroform/methanol=8:1 by volume), to afford 47 mg. of the desired compound as a yellow powdery solid, melting at 109°-112° C.; [α]22 -33.8° (C=0.5, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:11][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[CH2:13][NH2:14])=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=3)[CH2:13][NH:14][C:23]2=[O:24])=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CCNC(CN)c2ccc(C)c(C)c2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CCN2C(=O)NCC2c2ccc(C)c(C)c2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of N1-[2-(4-methoxyphenyl)ethyl]-1-(3,4-dimethylphenyl)-1,2-ethanediamine (10.6 g, 0.0356 mol) in dry DMF (55 mL) is added 1,1′-carbonyldiimidazole (6.4 g, 0.0395 mol). The reaction is stirred at 50° C. for 30 minutes, cooled, diluted with ethyl acetate (300 mL), and washed with 0.5 N HCl and brine. The organic phase is dried (MgSO4), and concentrated. The residue is re-crystallized from ethyl acetate (70 mL) to afford 7.5 g (65% yield) of the desired compound. 1H NMR (CDCl3) δ 7.16 (d, J=7.8 Hz, 2H), 7.05 (m, 4H), 6.84 (d, J=7.8 Hz, 2H), 4.50 (t, J=8.1 Hz, 1H), 3.82 (s, 3H), 3.73-3.65 (m, 2H), 3.27 (t, J=8.4 Hz, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 2.68 (m, 1H), 2.30 (s, 6H). MS 325 (MH+). Anal. Calcd. For C20H24N2O2 ¼H2O: C, 73.03; H, 7.51; N, 8.52. Found: C, 73.29; H, 7.19; N, 8.32.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([CH:16]=O)=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:36][NH2:37].[BH4-].[Na+]>C1COCC1.O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([CH2:16][NH:37][CH3:36])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C=O)c2s1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(CNC)c2s1
Yield: 91 %

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-formyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (140 mg, 0.28 mmol) was stirred in a 7M solution of methylamine in THF (8 mL) in a microwave tube equipped with a stirrer. The reaction was irradiated to 80° C. for 1 h in a CEM explorer microwave with stirring. After cooling, the solvents were removed under reduced pressure, the resulting residue dissolved in anhydrous MeOH (8 mL) and the reaction transferred to a round bottomed flask equipped with a calcium chloride drying tube. Sodium borohydride (43 mg, 1.12 mmol) was added and the reaction stirred at rt for 18 h. After this time LCMS indicated 70% conversion to the desired material. The reaction was diluted with water (20 mL), extracted with EtOAc (3×20 mL) and the combined organic extracts washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford the crude product as a glassy brown/grey solid 130 mg (91% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[O:17]1[CH2:20][C:19](=[O:21])[CH2:18]1.CC(=O)OCC>C1COCC1>[Br:1][C:2]1[C:7]([C:19]2([OH:21])[CH2:20][O:17][CH2:18]2)=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Br)c1
Reactant: O=C1COC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2c(Cl)ccnc2Br)COC1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a solution of 2-bromo-4-chloropyridine (14 g, 70 mmol) in dry THF (200 mL) was added LDA (42.0 mL, 84.0 mmol, 2.0 M) dropwise at −70° C. After stirring for 0.5 h at this temperature, a solution of oxetan-3-one (6.6 g, 90 mmol) in dry THF (40 mL) was added slowly and the reaction mixture was stirred at 0° C. for an additional 1 h. Saturated aqueous NH4CI (50 mL) and EA (200 mL) were added. The mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude material was purified by SGC eluting with DCM) to afford 148a as a yellow solid (8.8 g, 45%). MS: [M+H]+ 266.0.
Reaction SMILES: OO.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([C:24]4[NH:28][C:27]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:26]=5[N:25]=4)[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:6]=1[NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([O:41][C:42](=[O:44])[CH3:43])[CH2:37][CH2:36]1)#[N:4].CS(C)=[O:47].[OH-].[Na+]>C(O)C.O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([C:24]4[NH:28][C:27]5[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:26]=5[N:25]=4)[C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:6]=1[NH:34][C@H:35]1[CH2:36][CH2:37][C@H:38]([O:41][C:42](=[O:44])[CH3:43])[CH2:39][CH2:40]1)(=[O:47])[NH2:4]
Reactant: CC(=O)O[C@H]1CC[C@H](Nc2cc(-n3c4ccccc4c4c(-c5nc6ccc(F)cc6[nH]5)cccc43)ccc2C#N)CC1
Reactant: CS(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)O[C@H]1CC[C@H](Nc2cc(-n3c4ccccc4c4c(-c5nc6ccc(F)cc6[nH]5)cccc43)ccc2C(N)=O)CC1

Procedure:
In a 50 ml three-necked flask, 1.36 ml of 30% aqueous hydrogen peroxide are added to a mixture of 200 mg of acetic acid 4-{2-cyano-5-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]phenylamino}-trans-cyclohexyl ester, obtained in the preceding stage, in 7.5 ml of ethanol and 3 ml of dimethyl sulphoxide and 0.96 ml of 1M sodium hydroxide, and the mixture is stirred for ¼ hour at ambient temperature. 40 ml of distilled water are added and the mixture is extracted with 3 times 40 ml of ethyl acetate. The combined organic phases are washed with twice 40 ml of a saturated solution of sodium chloride, dried over magnesium sulphate and evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and methanol (96/4 by volume). 170 mg of acetic acid 4-{2-carbamoyl-5-[4-(6-fluoro-1H-benzimidazol-2-yl)-9H-carbazol-9-yl]phenylamino}-trans-cyclohexyl ester are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.Cl[C:42]([O:44][CH3:45])=[O:43].[Cl-].[NH4+]>C(Cl)Cl>[CH3:45][O:44][C:42]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:43]
Reactant: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Reactant: COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 21 h
Yield: 92.2 %

Procedure:
1.20 gram (2.65 mmol) of (−)-2-amino-2′-diphenylphosphino-1,1′-binaphthyl (1-1a) was dissolved in 53 ml of methylene chloride, followed by the addition of 0.26 ml (3.18 mmol) of pyridine and 0.23 ml (2.91 mmol) of methyl chloroformate under 0° C. The reaction mixture was stirred at room temperature for 21 hours. To the reaction solution, 40 ml of saturated aqueous solution of ammonium chloride was added and extracted with 100 ml of methylene chloride. The extract was washed with 80 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:4 mixture of ethyl acetate and hexane) to obtain 1.25 gram of the titled compound.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([S:14]C(=O)N(C)C)=[CH:6][C:5]=1C.[CH3:22]C(C[AlH]CC(C)C)C.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:10]([C:8]1([CH3:22])[CH:9]=[C:4]([CH2:3][OH:21])[CH:5]=[CH:6][CH:7]1[SH:14])([CH3:11])([CH3:12])[CH3:13]
Reactant: COC(=O)c1cc(C(C)(C)C)c(SC(=O)N(C)C)cc1C
Reactant: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)C1(C)C=C(CO)C=CC1S
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 12.2 g (39.4 mmol) of 5-tert-butyl-4-dimethylcarbamoylsulfanyl-2-methyl-benzoic acid methyl ester (prepared in Example DDD) in toluene (140 mL) cooled to -78° C. under nitrogen was added 1.0 M DIBAL/CH2Cl2 (236.6 mL), dropwise over a 2.5 hour period. The reaction mixture was stirred an additional 30 minutes at -78° C. following addition, then at 0° C. for 1 hour. Saturated aqueous citric acid solution (approximately 600 mL) was added very slowly and carefully. The mixture was then extracted twice with EtOAc; the organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.47 (s, 9 H), 2.27 (s, 3 H), 3.57 (s, 1 H), 4.63 (s, 2 H), 7.06 (s, 1 H), 7.32 (s, 1 H).