Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][S:22]([C:19]3[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=3)(=[O:24])=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)4-methylbenzenesulfonamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and p-toluene sulfonyl chloride in a similar manner as described above to give a tan solid (60% yield). 1H-NMR (CDCl3): δ 8.63 (s, 1H), 7.85 (d, 2H), 7.57 (m, 1H), 7.37 (d, 2H), 7.25 (m, 1H), 7.18 (d, 1H), 4.74 (d, 1H), 4.46 (m, 1H), 2.61 (m, 2H), 2.48 (s, 3H), 2.00-1.82 (m, 2H), 1.80-1.60 (m, 2H); MS m/z 419 (M−1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:35](=[O:37])[CH3:36])=[CH:7][C:6]=1[NH:13][C:14](=[O:34])[CH2:15][CH:16]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCC(CC(=O)Nc1cc(CN)ccc1C(C)(C)C)c1cc(OC)c(OC)c(OC)c1
Reactant: CC(=O)OC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CNC(C)=O)ccc1C(C)(C)C)c1cc(OC)c(OC)c(OC)c1

Procedure:
Following a similar procedure to that described in Example 144, but using N-(2-t-butyl-5-aminomethylphenyl)-3-(3,4,5-trimethoxyphenyl)octanamide (prepared as described in Preparation 72D) and acetic anhydride, the title compound was obtained as a colorless foam-like substance.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1>[OH-].[Na+]>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(-n2cc(C3=CCNCC3)c3ccc(Cl)cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Fc1ccc(-n2cc(C3CCNCC3)c3ccc(Cl)cc32)cc1
Reaction time: 5 h

Procedure:
Compound 1a (10 g) was added to 100 ml of NaOH solution and the base was subsequently extracted with dichloromethane (2×50 ml). The organic phase was dried (anh. MgSO4) and the solvent evaporated. The remaining oil was dissolved in 100 ml of acetic acid and PtO2 (300 mg) was added. The mixture was hydrogenated in a Parr apparatus for 5 hrs at 3 atm. The catalyst was then filtered off, and the acetic acid was evaporated. Dil. NaOH solution (200 ml) and ethyl acetate (200 ml) were added to the remaining oil. The organic phase was separated, dried (anh. MgSO4) and ethyl acetate was evaporated leaving the crude title compound 3a as an oil. The hydrochloride salt crystallized from ethanol. Mp 268° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8][OH:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:20][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:9][CH2:8][CH2:7][C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ncsc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2scnc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
To a solution of 4-methyl-5-thiazoleethanol (2 mL, 16.7 mmol) in CH2Cl2 (10 mL) and pyridine (10 mL) was added p-toluenesulfonyl chloride (3.5 g, 18.4 mmol) portionwise over 15 min. This mixture was stirred at ambient temperature for 18 h then was quenched with 5% aqueous HCl (15 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organics were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via column chromatography (SiO2, 50% hexanes/ethyl acetate) to give 2-(4-methylthiazol-5-yl)ethyl 4-methylbenzenesulfonate (3.24 g, 10.9 mmol, 65% yield). MS (DCI/NH3) m/z 298 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:20][N:19]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C@H:18]([CH2:49][C:50]([CH3:55])([CH3:54])[C:51](O)=[O:52])[CH2:17]2)=[CH:12][CH:11]=1)C>>[CH3:7][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[C@@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][CH2:35][O:36][CH3:37])[C:28]=4[CH:38]=3)[CH2:20][N:19]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[C@H:18]([CH2:49][C:50]([CH3:55])([CH3:54])[C:51]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[O:52])[CH2:17]2)=[CH:12][CH:11]=1
Reactant: CCOc1ccc([C@H]2C[C@@H](CC(C)(C)C(=O)O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: C1CNCCN1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)N4CCNCC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 102, piperazine is reacted with 3-[(2S,4R,5R)-4-(4-ethoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) to afford 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-1-piperazin-1-yl-propan-1-one which is subsequently deprotected according to general procedure A to afford the title compound.
Reaction SMILES: O.C(O)(C(F)(F)F)=O.[OH-].[Na+].[CH:11]([O:14][P:15]([CH2:21][O:22][C:23]1([CH2:26][O:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:25][CH2:24]1)(=[O:20])[O:16][CH:17]([CH3:19])[CH3:18])([CH3:13])[CH3:12]>CC(C)=O>[OH:27][CH2:26][C:23]1([O:22][CH2:21][P:15](=[O:20])([O:14][CH:11]([CH3:13])[CH3:12])[O:16][CH:17]([CH3:18])[CH3:19])[CH2:25][CH2:24]1
Reactant: CC(C)OP(=O)(COC1(COC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OP(=O)(COC1(CO)CC1)OC(C)C
Temperature: 25 °C

Procedure:
The compound of formula (10) obtained in Example 3 (59.15 g, 116.3 mmol) was dissolved in acetone [59.2 ml, 1 ml/g with respect to the compound of formula (10)], H2O (5.9 ml, 327.8 mmol) and TFA (26.52 g, 232.6 mmol) were added, and the mixture was stirred at room temperature. After the portion of the compound of formula (10) was confirmed 7% or less by HPLC, 3N aqueous NaOH solution [75 ml, 2.6 ml/g with respect to the compound of formula (10)] was added thereto, and acetone was removed therefrom by distillation under reduced pressure. The solid produced during the reaction was filtered off, and the filtrate was extracted twice with methylene chloride [118.3 ml×2, 2 ml/g with respect to the compound of formula (10)]. Thus obtained organic layer was concentrated under reduced pressure to give the title compound (2) [31.71 g, Purity 98%, Yield with respect to the compound of formula (10) 102.4%].
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:26][C:27]1([CH2:31]OS(C2C(C)=CC=CC=2)(=O)=O)[CH2:30][O:29][CH2:28]1.[Na+].[I-]>O.CN(C=O)C>[CH3:26][C:27]1([CH2:31][O:18][C:17](=[O:19])[C@@H:12]([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:30][O:29][CH2:28]1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Cc1ccccc1S(=O)(=O)OCC1(C)COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC1(C)COC1
Reaction time: 12 h

Procedure:
Cbz-L-leucine (2 g, 7.5 mmol) and Cs2CO3 (1.46 g, 4.5 mmol, 0.6 eq) were dissolved in water (20 mL). Water was then removed in vacuo, and the resulting oil was lyophilized for 12 h to give a white solid. To this solid were added 3-methyl-3-(toluenesulfonyl-oxymethyl)oxetane (oxetane tosylate) (1.8 g, 4.5 mmol), and NaI (224 mg, 1.5 mmol, 0.2 eq.) which were taken up in DMF (35 mL) and allowed to stir under nitrogen for 48 h. The DMF was then removed in vacuo, and the resulting solid was dissolved in EtOAc (60 mL) and washed with 10% NaHCO3 (20 mL) and saturated NaCl (10 mL) and dried over MgSO4. The solvent was removed under reduced pressure to yield yellow oil which was flash column chromatographed on 200 cm3 of silica gel using 3:1 hexanes:EtOAc as an eluant to give (2S)-2-benzyloxycarbonylamino-4-methyl-pentanoic acid 3-methyloxetan-3-ylmethyl ester (Cbz-Leu oxetane ester) as a yellow thick oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:12](=O)[NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH2:15]1)(C)(C)C.[OH-].[Na+].O>C1(C)C=CC=CC=1.C1COCC1>[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[CH2:15]1
Reactant: CN1CCN(C2CCCC(NC(=O)OC(C)(C)C)C2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CNC1CCCC(N2CCN(C)CC2)C1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
8.57 ml (8.57 mmol) of a 1 M solution of lithium aluminium hydride in toluene were dissolved in 8 ml THF and at ambient temperature slowly combined with 850 mg (2.86 mmol) of product from Example 4 (J) dissolved in 2 ml THF. The reaction solution was stirred for 2 hours at 75° C. Then 1N sodium hydroxide solution and water were added.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[NH:12][N:13]=C(C1C=CC=CC=1)C1C=CC=CC=1)#[N:2].S(=O)(=O)(O)O.[CH2:32](O)[CH2:33]C>>[NH2:2][C:1]1[C:3]2[O:7][C:6]([C:8]([O:10][CH2:11][CH2:32][CH3:33])=[O:9])=[CH:5][C:4]=2[NH:12][N:13]=1
Reactant: CCCO
Reactant: COC(=O)c1cc(NN=C(c2ccccc2)c2ccccc2)c(C#N)o1
Agent: O=S(=O)(O)O
Product: CCCOC(=O)c1cc2[nH]nc(N)c2o1
Reaction time: 4 h

Procedure:
To a solution of 56.01 g (0.1624 mol) of methyl 5-cyano-4-[2-(diphenylmethylene)hydrazino]-2-furoate in 1.12 L of n-propanol was slowly added 115 mL (2.1 mol) of 98% sulfuric acid. The resulting mixture was refluxed for 2 hours obtaining a clear brown solution. The reaction mass was concentrated under reduced pressure to a small volume, cooled to 0/+4° C. and slowly diluted with 1.1 L of 25% trisodium citrate dihydrate solution over a period of 90 min. under efficient stirring. The mixture (pH=4) was extracted three times with 600 mL of cyclohexane. The organic extracts were discarded while the aqueous layer was cooled to 0/+4° C. and brought to pH 6-7 by carefully adding 1 L of 10% aqueous sodium bicarbonate and, finally, 82 mL of N-methylmorpholine. The resulting suspension was aged for 4 hours at 0/+2° C. and then filtered and washed thoroughly with water affording, after drying, 21.35 g of product as light brown solid.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[N:18][O:19][CH3:20])[C:15]([NH2:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1/[C:14](=[N:18]\[O:19][CH3:20])/[C:15]([NH2:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CO/N=C(/C(N)=O)c1ccccc1Oc1ccccc1
Yield: 89 %

Procedure:
2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (E/Z=24/76) (5.05 g, 18.7 mmol) was dissolved in acetone (19 ml). Conc. hydrochloric acid (1.56 ml) was added, and the mixture was heated under reflux for 3 hours. After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ether. The ether layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give (E)-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide (4.50 g, Yield: 89.1%, E/Z=96/4).
Reaction SMILES: [CH3:1][S-:2].[Na+].CS(O[CH2:9][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11]1)(=O)=O>CN(C)C=O.O>[CH3:1][S:2][CH2:9][C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1
Reactant: C[S-]
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CSC)CC1
Temperature: 23 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Sodium methanethiolate (4.36 g, 62.30 mmol) was added to a stirred solution of ethyl 1-((methylsulfonyloxy)methyl)cyclopropanecarboxylate (6.92 g, 31.10 mmol) in N,N-dimethylformamide (62.30 mL) at 23° C. The resulting brown suspension was stirred at 23° C. for 18 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined organic layers were dried (MgSO4), filtered, and concentrated by rotary evaporation to afford the title compound as a brown oil (5.43 g, 100%): 1H NMR (300 MHz, CDCl3) δ 4.14 (q, J=7 Hz, 2H), 2.83 (s, 2H), 2.16 (s, 3H), 1.31 (dd, J=7, 4 Hz, 2H), 1.25 (t, J=7 Hz, 3H), 0.89 (dd, J=7, 4 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH:41]3[CH2:42][CH2:43][CH2:44][CH2:45]3)[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K61) (274 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (320 mg, 75%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]2[O:11][C:12]3([O:18][C:6]=2[C:5]=1[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[C:9]([CH3:10])=[CH:8][C:7]2[O:11][C:12]3([O:18][C:6]=2[C:5]=1[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3
Reactant: [H][H]
Reactant: Cc1cc2c(c(C)c1[N+](=O)[O-])OC1(CCCCC1)O2
Agent: [Pd]
Solvent: CCO
Product: Cc1cc2c(c(C)c1N)OC1(CCCCC1)O2
Yield: 90.3 %

Procedure:
Cyclohexanone 4-nitro-3,5-dimethyl-1,2-phenylene ketal (10.0 g) and 10% palladium on charcoal (1.0 g) in ethanol (200 ml) was shaken in a hydrogen atmosphere (50 p.s.i.) at 45° C. for 3 hours. The mixture was filtered through celite and evaporated to leave cyclohexanone 4-amino-3,5-dimethyl-1,2-phenylene ketal (8.0 g, 90%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:39][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[Cl:40][CH2:41][C:42](Cl)=[O:43].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:40][CH2:41][C:42]([N:36]1[CH2:37][CH2:38][CH:33]([N:28]2[CH:27]=[C:26]3[C:30]([CH2:31][CH2:32][C:24]4[C:23]5=[C:18]([NH:17][C:4]6[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]7[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=7)=[C:2]([Cl:1])[CH:3]=6)[N:19]=[CH:20][N:21]=[C:22]5[S:39][C:25]=43)=[N:29]2)[CH2:34][CH2:35]1)=[O:43]
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(C4CCNCC4)cc3-5)cc2Cl)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)N1CCC(n2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a suspension of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-piperidin-4-yl-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine 500 mg (0.89 mmol, 1 eq) in DCM (10 mL) was added chloroacetyl chloride (100 mg, 0.89 mmol, 1 eq) and triethylamine (90 mg, 0.89 mmol, 1 eq). It was stirred at rt for 3 h after which time it was diluted with water. It was then was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to yield the desired product (400 mg, 70%). 1H-NMR (DMSO-d6) δ 8.45 (broad, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.74 (d, 1H), 7.5 (dd, 1H), 7.44 (m, 1H), 7.29 (m, 2H), 7.20 (m, 2H), 5.23 (s, 2H), 4.45 (m, 4H), 3.93 (m, 1H), 3.38 (t, 2H), 3.24 (m, 1H), 2.92 (t, 2H), 2.83 (m, 1H), 2.08 (m, 2H), 1.97 (m, 1H), 1.80 (m, 1H). LCMS RT=3.68 min; [M+H]+=637.4.
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13].[CH3:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=O)=[CH:25][C:24]=1[C:32]([F:35])([F:34])[F:33]>>[F:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[C:2]1[N:1]=[C:27]([C:26]2[CH:30]=[CH:31][C:23]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]3[CH3:16])=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[O:15][N:14]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COC(=O)c1ccc(C(N)=NO)c(F)c1
Product: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(C(F)(F)F)c3)n2)c(F)c1

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 2 (106.09 mg; 0.50 mmol) and Intermediate 15 (143.64 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was suspended in ACN, filtrated and dried under vacuo, affording the title compound as a yellow solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.45 (dd, J=8.5, 1.9 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.34-8.29 (m, 1H), 8.01 (dd, J=8.1, 1.6 Hz, 1H), 7.94 (dd, J=10.9, 1.4 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 3.92 (s, 3H), 3.20-3.13 (m, 1H), 2.98-2.94 (m, 1H), 2.66-2.58 (m, 1H), 1.81-1.76 (m, 2H), 1.63-1.27 (m, 4H), 0.79 (d, J=6.0 Hz, 3H). HPLC (Method A) Rt 6.60 min (Purity: 70.1%).
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[N:8]([CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=O)[CH2:16]3)[C:7](=[O:24])[C:6]=12.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:56][O:57][C:58]1[CH:59]=[C:60]([CH:63]=[C:64]([O:68][CH3:69])[C:65]=1[O:66][CH3:67])[CH2:61][NH2:62]>CN(C)C=O>[CH3:69][O:68][C:64]1[CH:63]=[C:60]([CH:59]=[C:58]([O:57][CH3:56])[C:65]=1[O:66][CH3:67])[CH2:61][NH:62][C:21]([CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[N:11][CH:10]=3)[C:5]3=[N:4][O:3][C:2]([CH3:1])=[C:6]3[C:7]2=[O:24])[CH2:16]1)=[O:23]
Reactant: COc1cc(CN)cc(OC)c1OC
Reactant: Cc1onc2c1c(=O)n(C1CCCC(C(=O)O)C1)c1cnccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)C2CCCC(n3c(=O)c4c(C)onc4c4ccncc43)C2)cc(OC)c1OC
Yield: 86.9 %

Procedure:
Combine 3-(3-methyl-4-oxo-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-5-yl)-cyclohexanecarboxylic acid (50 mg, 0.15 mmol) with 1-[3-(dimethyl-amino)propyl]-3-ethylcarbodiimide hydrochloride (32 mg, 0.17 mmol), 1-hydroxy-7-azabenzo-triazole (23 mg, 0.17 mmol), N,N-diisopropylethyl amine (44 mg, 3.4 mmol) and 3,4,5-trimethoxy benzylamine (33 mg, 0.17 mmol) in N,N-dimethyl-formamide (4 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry the combined extracts over sodium sulfate. Concentrate and chromatograph over silica gel to give 66 mg (85%) of the desired product as a white solid. MS(ES): (M+1)+ 507.2, 508.2, 509.2 m/z.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[NH:10][CH:11]=[N:12][C:8]=2[CH:7]=1)=[O:4].[F:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1>C(OCC)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]2[CH2:22][CH2:23][N:24]([CH2:2][C:3]([NH:5][C:6]3[CH:14]=[CH:13][C:9]4[NH:10][CH:11]=[N:12][C:8]=4[CH:7]=3)=[O:4])[CH2:25][CH2:26]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C(CCl)Nc1ccc2[nH]cnc2c1
Solvent: CCOCC
Product: O=C(CN1CCC(Cc2ccc(F)cc2)CC1)Nc1ccc2[nH]cnc2c1

Procedure:
The title compound is prepared from 2-chloro-N-(1H-benzimidazol-5-yl)-acetamide (Example 151 a) and 4-(4-fluoro-benzyl)-piperidine according to the method described in Example 142b. Melting Point: 203.5-204.5° C. (diethylether)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[CH2:11]([OH:13])[CH3:12]>ClCCl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A stirred, 0° C. solution of 4-hydroxybenzonitrile (50.7 g, 426 mmol) in 1400 mL of dichloromethane and 75 mL anhydrous ethanol is treated with anhydrous hydrogen chloride gas (110 g) over 1.5 hours. This solution is stirred at room temperature for 64 hours and the resulting solids collected and washed with 500 mL diethyl ether and 2×1000 mL of ethyl acetate. The remaining solids (60.4 g) were dissolved in 1200 mL of water and the residual solids filtered. To the filtrate is added a solution of sodium hydroxide (12.57 g) in 150 mL water. The resulting white solid is filtered and washed with water to afford ethyl 4-hydroxybenzenecarboximidoate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:20][CH:19]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[CH:18]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[O:17]CC1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(NC[C@H]([C@@H](C1C=CC(Cl)=C(Cl)C=1)O)C(OC)=O)C1C=CC=CC=1>C1COCC1>[CH2:7]([NH:14][CH2:20][CH:19]([CH2:21][OH:22])[CH:18]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CN(Cc2ccccc2)C(=O)COC1c1ccc(Cl)c(Cl)c1
Agent: COC(=O)[C@H](CNCc1ccccc1)[C@H](O)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 119.9 %

Procedure:
To a solution of lithium aluminum hydride (644 mg) in THF (40 mL) was added dropwise a solution of (6RS,7RS)-4-benzyl-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-(3,4-dichlorophenyl)-1,4-oxazepan-3-one (4.17 g) in THF (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was cooled to −78° C., a solution of methyl (2R,3S)-2-[(benzylamino)methyl]-3-(3,4-dichlorophenyl)-3-hydroxypropanoate (10.8 g) in THF (80 mL) was added dropwise, and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was poured into ice water, and the mixture was stirred for 30 min, and filtered through celite. The filtrate was extracted twice with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (3.44 g).