Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[Cl:42][C:43]1[CH:44]=[C:45]([CH:53]=[CH:54][C:55]=1[Cl:56])CN1C=CC(N)=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:53]3[CH:45]=[CH:44][C:43]([Cl:42])=[C:55]([Cl:56])[CH:54]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: Nc1ccn(Cc2ccc(Cl)c(Cl)c2)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(Cl)c(Cl)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, the crude 1-(3,4-dichloro-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3,4-dichloro-benzyl)-1H-pyrazol-3-yl]-propionamide (133 mg, 79%) as a white solid: ESI-LRMS m/e calcd for C25H26Cl3N3O3S [M+] 553.1, found 554.2 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.22 (m, 2H, CH2), 1.42-1.90 (m, 8H, 4×CH2), 2.09-2.28 (m, 1H, CH), 3.24 (s, 3 H, SO2CH3), 3.57 (t, J=7.6 Hz, 1H, CH), 5.07 (s, 2H, NCH2), 6.71 (d, J=2.3 Hz, 1H, Ar), 6.95 (dd, Jo=8.2, Jm=2.0 Hz, 1H, Ar), 7.21 (d, Jm=2.0 Hz, 1H, Ar), 7.31 (d, J=2.3 Hz, 1H, Ar), 7.36 (d, Jo=8.2 Hz, 1H, Ar), 7.44 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.58 (d, Jm=1.7 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar), 8.14 (s, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([CH:22]=O)[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20](/[CH:22]=[N:25]/[OH:26])[CH:21]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(C=O)c2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(Br)cc(/C=N/O)c2)CC1

Procedure:
To the solution of tert-butyl 4-(3-bromo-5-formylphenoxy)piperidine-1-carboxylate (205 mg, 0.533 mmol) in ethanol (1.9 mL) and water (0.6 mL), hydroxylamine hydrochloride (40.8 mg, 0.587 mmol) and sodium acetate (61.3 mg, 0.747 mmol) were added sequentially, then the resulting solution was refluxed for 1 hour. The most organic solvent was removed in vacuo and the solution was diluted with water. The resultant precipitate was collected and dried under vacuum to give the desired product as white solid. LCMS (M+H)+: 399.1, 401.1.
Reaction SMILES: Cl[Si]1(Cl)CC(C)[CH2:3]1.[C:8]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])=[CH2:9]>>[CH3:13][Si:12]1([O:11][C:8]([CH3:10])=[CH2:9])[CH2:15][CH2:3][CH2:14]1
Reactant: CC1C[Si](Cl)(Cl)C1
Reactant: C=C(C)O[Si](C)(C)C
Product: C=C(C)O[Si]1(C)CCC1

Procedure:
In accordance with the general procedure of Example 1, when 1,1-dichloro-3-methylsilacyclobutane and isopropenoxytrimethylsilane are reacted it is predicted that the title compound is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.CCOC(C)=O>CCO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#CCO)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CCCO)cc2)CC1
Yield: 71 %

Procedure:
To a solution of tert-butyl 4-(4-(3-hydroxyprop-1-ynyl)phenyl)piperazine-1-carboxylate (3.2 g, 10.11 mmol) in EtOH (253 mL) was added EtOAc (200) and Pd/C (10% mol on carbon, 3.2 g). The reaction mixture was shaken at 50 psi of H2 atm. overnight. The next day, the catalyst was removed from the reaction mixture via a filtration over a pad of celite and the filtrate was concentrated to yield a crude oil. Purification of the crude material using silica gel chromatography (gradient method of 0%-100% EtOAc in hexanes) yielded tert-butyl 4-(4-(3-hydroxypropyl)phenyl)piperazine-1-carboxylate as an off-white solid (2.3 g, 71% yield). 1H NMR (300 MHz, CDCl3): δ 7.11 (d, 2H, J=8.7 Hz), 6.89 (d, 2H, J=8.7 Hz), 3.67 (br t, 2H, J=6.4 Hz), 3.58 (dd, 4H, J=5.2, 5.1 Hz), 3.09 (dd, 4H, J=5.2, 5.0 Hz), 2.65 (dd, 2H, J=8.0, 7.4 Hz), 1.87 (m, 2H), 1.49 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 154.9, 149.7, 133.9, 129.3, 117.1, 80.1, 62.4, 49.9, 44.1, 34.5, 31.3, 28.6; HRMS calcd for C18H28N2O3: 321.21727 found 321.2174.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11]2)=[CH:6][CH:5]=1>CO.[OH-].[Na+]>[O:15]=[C:12]1[CH2:13][CH2:14][C@H:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1
Reactant: COC(=O)c1ccc([C@H]2CCC(=O)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CC[C@H](c2ccc(C(=O)O)cc2)C1
Yield: 100.3 %

Procedure:
(S)-4-(3-Oxo-cyclopentyl)-benzoic acid methyl ester (preparation 19) (10.2 mmol, 2.25 g) was taken up in MeOH (6 mL) and NaOH (2N, 6 mL), the reaction mixture stirred at r.t. for 2 h. Then the MeOH was evaporated and the reaction mixture diluted with water, then neutralized with HCl (2N) to pH 5 and extracted with DCM. Dried over Na2SO4 and concentrated in vacuo to yield the title compound (2.09 g, 99%). 1H NMR (300 MHz, DMSO) δ 12.83 (br s, 1H), 7.94-7.84 (m, 2H), 7.45 (d, 2H), 3.55-3.39 (m, 1H), 2.65-2.52 (m, 1H), 2.41-2.21 (m, 4H), 2.03-1.84 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16]CC)=O)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([NH2:19])=[O:16])=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(Cc2ccccc2)cn1
Reactant: N
Product: NC(=O)c1ccc(Cc2ccccc2)cn1
Reaction time: 24 h

Procedure:
To one gram of ethyl 5-benzylpicolinate, 10 ml. of 28% aqueous ammonia were added. After allowing the mixture to stand at room temperature for 24 hours, crystals formed were collected by filtration and recrystallized from ethanol to obtain 0.6 g of 5-benzylpicolinic acid amide as colorless crystals of a melting point of 193°~196° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:5][C:6]([S:17][CH3:18])=[N:7][C:8]=2[CH2:9][CH2:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=1)=[N:5][C:6]([S:17][CH3:18])=[N:7]2
Reactant: CCOC(=O)C1=C(N)c2c(nc(SC)nc2-c2cccc([N+](=O)[O-])c2)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2nc(SC)nc(-c3cccc([N+](=O)[O-])c3)c2c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of crude ethyl 5-amino-2-methylthio-4-(3-nitro-phenyl)-7,8-dihydro-quinazoline-6-carboxylate (example 27d, 1.19 g) in CH2Cl2 (31 ml) was cooled to 0° C. A solution of DDQ (1.14 g) in toluene (31 ml) was added dropwise, the ice-bath removed and the solution was stirred for an additional 30 min at room temperature. The mixture was diluted with CH2Cl2 (ca 100 ml) and washed with a saturated aqueous solution of NaHCO3 (3×100 ml) and brine (2×50 ml). The combined aqueous layers were back-extracted with CH2Cl2. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel using hept/EtOAc=9/1 to 3/2 (v/v) as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]CC)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-:20].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]([NH2:14])=[O:20])=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1cnn(-c2cccc(Br)c2)c1C#N
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1cccc(Br)c1

Procedure:
A 14 g. portion of ethyl 1-(3-bromophenyl)-5-cyano-4-pyrazolecarboxylate was hydrolyzed by stirring under reflux in 200 ml. of ethanol with 6 g. of potassium hydroxide for 2 hours. The mixture was then poured over ice, acidified and filtered, and the solids were crystallized from ethanol/water and dried at 168° to obtain 10 g. of the desired product, m.p. 215°-217° dec. The product was identified by NMR analysis in CDCl3 /DMSOd6. δ7.06 (s,1), carboxamide; 7.30-7.64 (m,4), aromatic; 8.08 (s,1), pyrazole; 9.10 (s,1), carboxamide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[Si:21]([O:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])([C:34]([CH3:37])([CH3:36])[CH3:35])([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>O1CCOCC1>[Si:21]([O:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH:43][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[S:9])=[CH:6][N:5]=[C:4]([CH3:13])[N:3]=1)([C:34]([CH3:35])([CH3:36])[CH3:37])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)[Si](OCc1cccc(N)c1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=S)c1cnc(C)nc1Nc1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Temperature: 50 °C
Yield: 103.4 %

Procedure:
A solution of 2.32 g (10 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate in 30 ml of 1,4-dioxan was treated with 1.4 ml (10 mmol) of triethylamine and 4.7 g (13 mmol) of 3-(tert-butyldiphenylsilyloxymethyl)aniline. The mixture was heated to 50° C. for 18 hours and then evaporated. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of 2M aqueous hydrochloric acid. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford 5.6 g (100%) of ethyl 4-[3-(tert-butyldiphenylsilyloxymethyl)anilino]-2-methylthiopyrimidine-5-carboxylate as a colorless oil. [Mass spectrum (ESI) MH+ =558].
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:6]([CH3:19])[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[C:15]([O:14][C:12]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][C:6]=1[CH3:19])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
4-(tert-Butoxycarbonylamino-methyl)-3-methyl-benzoic acid methyl ester from Example E2h.3 (1.04 g, 3.7 mmol) was dissolved in dioxan (20 ml). 1N NaOH solution (5.6 ml, 5.6 mmol) was added and the mixture was stirred for 18 h at room temperature then concentrated in vacuo. The residue was redissolved in EtOAc, washed with 1N KHSO4 then brine, dried and concentrated in vacuo to yield the title compound (800 mg, 81%).
Reaction SMILES: [NH2-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].[CH3:10][O:11][CH2:12][C:13](OC)=[O:14].O>C(O)(=O)C>[CH3:10][O:11][CH2:12][C:13](=[O:14])[CH2:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[CH3:3]
Reactant: CC(=O)C(C)(C)C
Reactant: COCC(=O)OC
Agent: [NH2-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCC(=O)CC(=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 9.74 g (250 mmol) of sodium amide, and the flask was purged with argon. Then, 80 mL of toluene was placed in the flask. Subsequently, 25.0 g (249.6 mmol) of 3,3-dimethyl-2-butanone was slowly dropped into the flask, and the resulting mixture was stirred for 15 minutes. Into the flask was further dropped 10.4 g (99.9 mmol) of methyl methoxyacetate, and the mixture was stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 50 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, neutralized with acetic acid, and subjected to extraction with ether. The ether extract was washed with water, dried over hydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (65° C., 426 Pa) to give 5.90 g (yield: 34%) of 1-methoxy-5,5-dimethyl-2,4-hexanedione as colorless liquid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([S:6]([OH:9])(=[O:8])=[O:7])[CH3:5].[OH2:10]>O1CCOCC1>[S:6]([CH:4]([CH3:5])[CH2:3][CH2:2][O:1][S:6]([CH:4]([CH2:3][CH2:2][OH:1])[CH3:5])(=[O:7])=[O:10])([OH:9])(=[O:8])=[O:7]
Reactant: O
Reactant: CC(CCO)S(=O)(=O)O
Solvent: C1COCCO1
Product: CC(CCOS(=O)(=O)C(C)CCO)S(=O)(=O)O

Procedure:
Sulfoalkylating agent, obtainable by heating 4-hydroxy butane-2-sulfonic acid or 3-methyl-1,3-propane sultone to a temperature in the region of from 80° to 180° C. in the presence of water in an amount of from 1 to 4 moles per mol of 4-hydroxy-butane-2-sulfonic acid or 3-methyl-1,3-propane sultone, and characterized by the following 13C-NMR-shifts (ppm, relative to TMS=0, in the presence of dioxane): 15.4; 31.7; 34.4; 53.6; 60.0 and 68.5.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:22]1[S:23][C:24]([CH2:27][N:28]=[N+]=[N-])=[CH:25][CH:26]=1)#[N:21]>C1COCC1.O>[C:20]([C:22]1[S:23][C:24]([CH2:27][NH2:28])=[CH:25][CH:26]=1)#[N:21]
Reactant: N#Cc1ccc(CN=[N+]=[N-])s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CN)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 166.4 %

Procedure:
Triphenylphosphine (Aldrich, 5.7 g) was added to a solution of 2-cyano-5-(azidomethyl)thiophene (compound 3-4, 2.5 g, 10 mmol) in THF (Aldrich, 40 ml) and water (10 ml) at 0° C. The solution was allowed to warm to room temperature and stirred at ambient temperature for 10 hours. RP-HPLC purification gave the title compound (2.3 g, 94%). MS (electrospray): 139 (M+1); 1H NMR (CDCl3): δ 4.01 (s, 2H), 4.75 (br s, 2H, NH2), 6.82 (d, 1H, J=3.5 Hz), 7.08 (d, 1H, J=3.5 Hz).
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:19][O:20][C:21]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>CCOC(C)=O.CC(O)C>[CH:8]1[C:9]2[NH:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[C:5]([O:4][CH2:3][C@@H:2]([OH:1])[CH2:18][NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:21]=2[O:20][CH3:19])=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccc(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)c(OC)c1
Temperature: 85 °C
Yield: 47.6 %

Procedure:
To a solution of (S)-(+)-4-(2,3-Epoxypropoxy)-carbazole (7.56 g, 0.031 mole) in EtOAc/IPA (40/80 mL) was added 2,4-dimethoxybenzylamine (9.48 mL, 0.063 mole) and the reaction mixture was slowly heated to 80-90° C. and then refluxed for 5 hours. Subsequently the reaction mixture was cooled to room temperature and purified following the procedure similar to one described in step 11 for the synthesis of example 23, to afford the desired compound as colorless solid (6 g, 48%) with m.p: 152-154° C. 1H NMR (400 MHz, CDCl3): δ 2.17 (s 1H), 2.88-2.92 (m, 1H), 2.98-3.00 (m, 1H), 3.74-3.87 (m, 8H), 4.18-4.32 (m, 3H), 6.38-6.45 (m, 2H), 6.67 (d, 1H, J=8.0 Hz), 7.05 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.18-7.40 (m, 4H), 8.08 (s, 1H), 8.21 (d, 1H, J=8.0 Hz). MS m/z: 407.1 (M+1). Chiral purity: 99.96%
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[CH2:5][CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH2:5][CH2:4][O:3]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CN1CCOC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCOC1=O)OCc1ccccc1
Reaction time: 3 h
Yield: 30.8 %

Procedure:
To a stirred solution of 1.0 g (6.9 mmol) of (2-oxo-1,3-oxazolidin-3-yl)acetic acid in 10 mL of anhydrous DMF was added 1.0 g (7.6 mmol) of potassium carbonate followed by 1.0 mL (8.3 mmol) of benzyl bromide. The reaction mixture was stirred for 3 h then quenched with water. The aqueous phase was extracted with ethyl acetate (3×25 mL) and the combined organics were washed with water (2×10 mL), brine (10 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with 50% ethyl acetate in hexanes to afford the title compound as a white solid 0.50 g (31%). LC-MS: m/z (ES) 236 (MH)+.
Reaction SMILES: [CH:1]1([C:10]([O:12]CC)=[O:11])[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C1(C(OCC)=O)C2(CCCCC2)C1>>[CH:1]1([C:10]([OH:12])=[O:11])[C:3]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1
Reactant: CCOC(=O)C1CC12CCCCCC2
Agent: CCOC(=O)C1CC12CCCCC2
Product: O=C(O)C1CC12CCCCCC2

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 39B for the product from Example 1A. 13C NMR (CDCl3, 100 MHz) δ 23.7, 26.2, 26.4, 27.2, 27.9, 28.0, 28.4, 31.2, 33.4, 33.5, 40.1, 179.3; MS m/z 168 (M)+.
Reaction SMILES: [F:1][C:2]1[C:7](I)=[N:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1>C1COCC1>[F:1][C:2]1[C:7]([C:12]2([OH:15])[CH2:13][CH2:14][O:9][CH2:10][CH2:11]2)=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1nccnc1I
Reactant: O=C1CCOCC1
Solvent: C1CCOC1
Product: OC1(c2nccnc2F)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-3-iodopyrazine (1 g, 4.46 mmol) in THF (4.46 mL) at 0° C. was added isopropylmagnesium chloride lithium chloride complex, 1.0M solution in THF (4.87 mL, 4.46 mmol). The resulting mixture was stirred for 5 min before addition of dihydro-2H-pyran-4(3H)-one (0.410 mL, 4.46 mmol). Reaction mixture was allowed to warm to room temperature and stirred overnight. Purification by Biotage (0-100% EtOAc/hexane) produced the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([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)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH2:55])=[CH:49][CH:48]=2)[CH:42]=[CH:43][C:44]=1[O:45][CH3:46]>>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:9](=[O:11])[NH:55][CH2:54][CH2:53][C:50]1[CH:51]=[CH:52][C:47]([C:41]2[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:39]([O:38][CH3:37])[CH:40]=2)=[CH:48][CH:49]=1)[CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(-c2ccc(CCN)cc2)cc1OC
Reactant: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Product: COc1ccc(-c2ccc(CCNC(=O)C(CC(=O)NOC(c3ccccc3)(c3ccccc3)c3ccccc3)CC(=O)OC(C)(C)C)cc2)cc1OC

Procedure:
This compound was prepared by reacting the compound of Example 63 with the compound of Example 35.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:19])=[O:5].[CH2:29](OC(OCC)OCC)C.C(O)(=O)C>C(O)C>[CH:16]1([NH:15][C:13](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([CH3:19])=[C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:23][CH:22]=[C:21]([O:24][CH2:25][C:26]([CH3:28])=[CH2:27])[CH:20]=4)[N:1]=[CH:29]3)[CH:12]=2)[CH2:17][CH2:18]1
Reactant: CCOC(OCC)OCC
Reactant: C=C(C)COc1ccc(N)c(C(=O)Nc2cc(C(=O)NC3CC3)ccc2C)c1
Solvent: CC(=O)O
Solvent: CCO
Product: C=C(C)COc1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Temperature: 25 °C

Procedure:
A solution of 2-amino-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-5-[(2-methylprop-2-en-1-yl)oxy]benzamide (3.6 g), triethylorthoformate (4.6 ml) and acetic acid (0.6 ml) in ethanol (50 ml) was heated at reflux for 18 hours. The reaction was cooled to room temperature and concentrated. The residue was partitioned between aqueous potassium carbonate solution (50 ml) and ethyl acetate (200 ml). The organic extracts were washed with brine (100 ml), dried (magnesium sulfate) and concentrated to give the crude N-cyclopropyl-4-methyl-3-[6-[(2-methylprop-2-en-1-yl)oxy]-4-oxoquinazolin-3(4H)-yl]benzamide as an oil (2.5 g) which was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([OH:17])(C(OC)=O)[CH:8]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:7][C:6]=2[CH:26]=1.[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:9]([OH:17])[C@@H:8]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:7][C:6]=2[CH:26]=1
Reactant: COC(=O)C1(O)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: COc1ccc([C@H]2Cc3cc(Cl)ccc3NC(=O)[C@H]2O)cc1
Temperature: 25 °C

Procedure:
A solution of 7-chloro-1,3,4,5-tetrahydro3-hydroxy-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (0.5 g, 1.33 mmole) and lithium iodide (0.178 g, 1.33 mmole) in dry pyridine (20 ml) was refluxed under argon until complete conversion to product by TLC. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in chloroform and extracted twice with 1N hydrochloric acid, once with saturated sodium chloride, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was triturated with ether to yield 0.22 g of the cis product.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[O:22]=[C:11]1[N:10]([CH2:9][CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]2)[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: N#Cc1ccc2c(c1)N(CC[C@H]1CC[C@H](N)CC1)C(=O)CO2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)N(CC[C@H]1CC[C@H](NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2

Procedure:
4-[2-(Trans-4-aminocyclohexyl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 77), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted following the procedure described for Example 21 to give the product in 7% yield, as an off-white solid.