Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:38][NH:39][C:40]1=[N:41][C:42](=[O:52])[S:43]/[C:44]/1=[CH:45]\[CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C)C=O.O.C(N(CC)CC)C>[CH3:38][NH:39][C:40]1=[N:41][C:42](=[O:52])[S:43]/[C:44]/1=[CH:45]\[CH:46]1[CH2:51][CH2:50][N:49]([C:11]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[O:13])[CH2:48][CH2:47]1
Reactant: CNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: Cc1c(C(=O)O)oc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC1=NC(=O)S/C1=C\C1CCN(C(=O)c2oc3ccccc3c2C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
To a solution of 3-methyl-1-benzofuran-2-carboxylic acid (19.4 mg) in N,N-dimethylformamide (1 mL) were added 1-hydroxybenzotriazole (16.2 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23 mg), and the mixture was stirred at 0° C. for 5 min. To the reaction mixture were added triethylamine (0.28 mL) and (5Z)-4-(methylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (29.8 mg), and the mixture was further stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (19.3 mg).
Reaction SMILES: Cl[C:2](=[N:11][OH:12])[C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:10].C(N(C(C)C)CC)(C)C.O=[C:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[Cl:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:3]=1[C:2]1[C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([CH3:29])[O:12][N:11]=1
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(-c2c(Cl)cccc2Cl)noc1C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a solution of 0.1 g (0.4455 mmol) alpha-Chloro-2,6-dichlorobenzaldoxime in 5 mL methyl 3-oxobutanoate, 0.11 mL (1.5 eq) diisopropylethlamine were added. The mixture was stirred for 24 h then ethylacetate was removed in the vacuo. The residue was dried under high vacuo and the crude product was triturated in water until it became solid. The solid was filtered off and further purified by recrystallization from a water-methanol mixture. The crystals were filtered off, washed with water and dried under reduced pressure to afford 248 mg (87%) of methyl 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate. Result of LC/MS [M+H]+: 286.12; 1H NMR (DMSO-d6; CCl4): 2.77 (3H, s, CH3-isooxazole), 3.28 (3H, s, CH3-methoxy), 7.54-7.65 (3H, m, aromatic)
Reaction SMILES: [Cl:1][C:2]([Cl:5])([Cl:4])[CH3:3].[C:6]([Cl:9])([Cl:8])=[CH2:7]>>[Cl:1][C:2]([Cl:5])([Cl:4])[CH2:3][C:6]([Cl:9])([Cl:8])[CH3:7]
Reactant: CC(Cl)(Cl)Cl
Reactant: C=C(Cl)Cl
Product: CC(Cl)(Cl)CC(Cl)(Cl)Cl

Procedure:
2,2,4,4,4-Pentafluorobutane is another undesirable by-product of the fluorination of 1,1,1-trichloroethane. I believe that it is formed by the reaction between 1,1,1-trichloroethane and vinylidene chloride, followed by the reaction of additional 1,1,1-trichloroethane with vinylidene chloride to give 1,1,1,3,3-pentachlorobutane. Grigor'ev et al., Izv. Akad. Nauk. SSSR. Ser. Khim., 6, 1333-6 (1980). Hydrofluorination of the latter produces 2,2,4,4,4-pentafluorobutane.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22]CC)=[O:21].[OH-].[Na+].Cl>CCO.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3)c2c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)O
Temperature: 0 °C
Yield: 99.4 %

Procedure:
To a solution of ethyl 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (Example 36a, 110 g, 0.335 mol) in EtOH (450 mL) was added a solution of NaOH (33.5 g, 0.837 mol) in water (200 mL) at room temperature. The reaction mixture was then refluxed overnight. The reaction solution was cooled down to 0° C. and carefully neutralized with 4N HCl to pH 7. The resultant solution was concentrated under reduced pressure to remove most of the EtOH. The precipitate was collected by filtration, and re-dissolved in EtOH (4 L) at 65° C. and treated with activated charcoal (5 g) for 0.5 h. The charcoal was removed by filtration over celite, and the filtrate was concentrated. The precipitate was collected by filtration, washed with cold water, and dried under vacuum at 60° C. overnight to give the title compound as a white solid (100 g, 99%). M.p.: 220.0-221.5° C. 1H NR (400 MHz, DMSO-d6) δ 1.28-1.72 (m, 8H), 2.00-2.04 (m, 2H), 2.75 (s, 3H), 4.69-4.71 (m, 1H), 7.10-7.12 (d, J=8.0 Hz, 1H), 7.24-7.26 (d, J=8.0 Hz, 1H), 7.65 (t, J=8.0 Hz, 1H), 12.80 (brs, 1H). MS 301 (MH+). Elemental Analysis Calculated (Found) for C17H20N2O3: C, 67.98% (67.74%); H, 6.71% (7.01%); N, 9.33% (9.40%).
Reaction SMILES: [C:1]1([CH2:7][N:8](CC2C=CC=CC=2)[CH2:9][C@@H:10]([NH:12][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>[Pd].CCO>[CH3:11][C@H:10]([NH:12][C@H:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])[CH2:9][NH:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@H](C)N[C@@H](C)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@H](C)N[C@@H](C)CNCc1ccccc1
Yield: 43.2 %

Procedure:
A mixture of methyl N-{(1S)-2-[bis(phenylmethyl)amino]-1-methylethyl}-L-alaninate (J. Org. Chem. 1995, 60, 4177-4183) (2.156 g, 6.33 mmol), concentrated hydrochloric acid 37% (0.805 mL), 5% palladium on carbon (0.863 g), and EtOH (40 mL) was hydrogenated under a hydrogen balloon for 48 h. The mixture was filtered through Celite, and the solids were washed with MeOH and CH2Cl2. The filtrates were combined and concentrated under reduced pressure. The residue was redissolved in EtOH (55 mL), p-toluenesulfonic acid (0.344 g) was added, and the mixture was heated at reflux for 16 h. The mixture was concentrated under reduced pressure and partitioned between CH2Cl2 and NaHCO3. The aqueous layer was back extracted with CH2Cl2, and the combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (9:1, CH2Cl2:MeOH) to provide methyl N-{(1S)-1-methyl-2-[(phenylmethyl)amino]ethyl}-L-alaninate (685 mg, 50%). LCMS: (M+H)+: 129.1. The leftover aqueous layer was extracted further with 40% isopropanol in CHCl3 twice, and the combined organic layers were dried (Na2SO4), filtered, and concentrated to yield (3S,5S)-3,5-dimethyl-2-piperazinone (306 mg, 38%). LCMS: (M+H)+: 129.1.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl.Cl[CH2:37][C:38]1[N:39]=[C:40]([CH3:43])[S:41][CH:42]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:37][C:38]3[N:39]=[C:40]([CH3:43])[S:41][CH:42]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: Cc1nc(CCl)cs1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Agent: Cl
Product: Cc1nc(CN2CN(c3ccccc3Cl)C3(CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC3)C2=O)cs1

Procedure:
The title compound, MS: m/e=617.0 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 4-chloromethyl-2-methylthiazole hydrochloride.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].O.NN.N.C(Cl)Cl>CO.[Ni]>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Ni]
Agent: N
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CCN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 98.9 %

Procedure:
A suspension of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (0.375 g, 1.382 mmol) in dry methanol (10 mL) was treated with Raney-nickel (0.1 g, 0.351 mmol), followed by hydrazine hydrate (0.672 mL, 13.82 mmol) at room temperature. The resulting mixture was placed in a pre-heated oil bath and refluxed for 5 min. (TLC basis, 2 M NH3 in MeOH:CH2Cl2, 5:95). The reaction was brought to room temperature, filtered through celite bed and washed with methanol (3×5 mL). The combined methanol layer was evaporated and crude was purified by flash column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine (0.33 g, 99%) as a foam. 1H NMR (DMSO-d6) δ 10.60 (s, 1H), 7.15 (d, 1H, J=2.7 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.00 (d, 1H, J=1.5 Hz), 6.48 (dd, 1H, J=2.1, 8.5 Hz), 5.98 (s, 1H), 4.48 (s, 2H), 3.10-3.04 (m, 2H), 2.59 (t, 2H, J=5.4 Hz), 2.54-2.39 (m, 4H, merged with DMSO peak), 1.06 (t, 3H, J=7.2 Hz); EI-MS (m/z, %): 241 (M+, 100).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:9]=1[C:10]([OH:12])=[O:11]>C(Cl)(Cl)Cl>[Cl:4][C:16]1[C:8]([O:7][CH3:6])=[C:9]([C:13]([O:17][CH3:18])=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cccc(OC)c1C(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)c(OC)c1C(=O)O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 16.2 ml (0.2 mol) of sulphuryl chloride in 100 ml of chloroform is added dropwise while stirring to a solution of 36.4 g (0.2 mol) of 2,6-dimethoxybenzoic acid in 300 ml of chloroform. The mixture is heated for 0.5 h at 50° C. and left overnight at room temperature. The solvent is evaporated and the residue recrystallized from isopropyl ether--light petroleum. Yield: 35.4 g, m.p. 132°-33° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.[CH:27]1[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:34]>>[Cl:26][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:33][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:34])[CH:27]=2)=[N:3][CH:4]=1
Reactant: Cc1cccc(O)c1
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Product: Cc1cccc(Oc2ncc(Cl)cc2C(=O)N[C@@H](C)c2ccc(C(=O)OC(C)(C)C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from tert-butyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 45) and m-cresol: MS (ESI) m/z 467 (M+H)+, 465 (M−H)−.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[OH:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)=[CH:18][CH:19]=1
Reactant: NCc1ccc(CO)cc1
Reactant: O=C(O)c1ccc(N2CCCC2)cc1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C(NCc1ccc(CO)cc1)c1ccc(N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a mixture of 4-pyrrolidin-1-ylbenzoic acid (2.0 g, 10.5 mmol), (4-aminomethylphenyl)methanol (4.3 g, 31.4 mmol), 1-hydroxybenzotriazole (1.7 g, 12.6 mmol), and DMAP (256 mg, 2.1 mmol) in pyridine (50 mL) was added EDC (3.0 g, 15.7 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and an aqueous NaHCO3 solution (50 mL) was added. The mixture was extracted with 5% MeOH in CHCl3 (150 mL×2), and the organic layer was dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by MPLC on silica gel (3% MeOH in CHCl3) to afford the titled compound (2.56 g, 79%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:35][CH2:34]4)=[N:21][N:22]3[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:24]=3)[C:20]([CH:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([OH:42])=[O:41])[CH2:35][CH2:34]3)=[N:21]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(Cl)cc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(c2nn(Cc3ccc(Cl)cc3)c3cc(/C=C/C4CCNCC4)ccc23)CC1
Yield: 86 %

Procedure:
A solution of 4-{2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1-(4-chloro-benzyl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (0.152 g, 0.234 mmol) in trifluoroacetic acid (4 ml) was stirred at 23° for 3 h. The solvent was removed in vacuo and the residue was triturated with ether to give the title compound as an ivory solid (0.148 g, 86%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[N:13][C:14]=3[C:5]=2[N:4]=[C:3]1[CH2:15][OH:16]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[N:13][C:14]=3[C:5]=2[N:4]=[C:3]1[CH:15]=[O:16]
Reactant: Cn1c(CO)nc2c3ncccc3ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1c(C=O)nc2c3ncccc3ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.9 %

Procedure:
To a solution of (3-methyl-3H-imidazo[4,5-h]quinolin-2-yl)methanol (560 mg, 2.62 mmol) in DCM (10 mL) was added manganese (IV) oxide (2.28 g, 26.2 mmol). The mixture was stirred at room temperature for 12 h. The solid was removed by filtration and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 2:1) to give 3-methyl-3H-imidazo[4,5-h]quinoline-2-carbaldehyde as a yellow solid (370 mg, yield: 67.5%). ESI MS: m/z 212 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11]([CH2:12][NH:13][CH2:14][C:5]=2[CH:4]=1)=[N:10][N:9]=[C:8]3[C@H:15]1[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]3[C:11](=[N:10][N:9]=[C:8]3[C@H:15]3[CH2:16][CH2:17][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:19][CH2:20]3)[CH2:12][N:13]([C:34](=[O:36])[CH3:35])[CH2:14][C:5]=2[CH:4]=1
Reactant: CC(=O)Cl
Reactant: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CNC3)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(C)C)CC2)C1
Reaction time: 19 h

Procedure:
To a solution of trans-8-chloro-1-(4-isopropoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene hydrochloride (0.080 g, 0.20 mmol) and triethylamine (0.059 ml, 0.42 mmol) in dichloromethane (5 ml) was added acetyl chloride (0.016 ml, 0.22 mmol) at room temperature. After stirring for 19 h the reaction mixture was concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.062 g, 77%) as white solid. MS m/e: 403 (M+H+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.N1C=CC=CC=1>[CH:26]1([C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:25][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]5[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)C4CCCCC4)ncc3[nH]2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCC4)cc3)[nH]c2cn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a stirring solution of 10 (0.080 g, 0.24 mmol) in dry THF/Pyridine (10 ml/0.300 ml) cyclohexane carbonyl chloride (0.060 ml, 0.38 mmol) was added and stirred at room temperature for 4 h. The reaction mixture was quenched with water and stirred for 30 min. The yellow solid was filtered, dried, and purified through a bed of SiO2 gel. Elution with ethyl acetate afforded the desired product 11 as light yellow solid 0.055 g (51%). Mp. 235° C.; 1HNMR (DMSO-d; 500 MHz): δ 12.99 (1H, brs, NH), 10.27 (1H, brs, NH), 10.07 (1H, brs, NH), 8.61 (1H, brs), 8.27 (1H, brs), 8.07 (2H, d, J=8.0 Hz), 7.79 (2H, d, J=9.0 Hz); 2.52 (1H, m), 2.36 (1H, m), 1.83-1.17 (20H, m); EIMS m/z: 446.5 (M+1) 444.6 (M−1); Anal. (C26H31N5O2.0.91H2O) C, H, N
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([CH:17]=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>C1COCC1>[N:19]1([CH2:17][C:15]2[S:14][C:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=3[CH:16]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2sc(CN3CCCCC3)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carbalde-hyde (440 mg, 1.65 mmol) and piperidine (0.18 ml, 1.81 mmol) were dissolved in THF (10 ml), and NaBH(OAc)3 (523 mg, 2.47 mmol) and glacial acetic acid (94 μl, 1.65 mmol) were added. This mixture was stirred under a nitrogen atmosphere at room temperature for 24 hours. The solvent was then distilled off in vacuo and the residue was taken up in ethyl acetate (25 ml). The solution obtained was washed with NaHCO3 solution and NaCl solution and the combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. The crude product (580 mg) was employed directly in the next stage without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[C-]#N.[Na+].[C:28](#[N:30])C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CCCCCC.CCOC(C)=O>[Cl:11][C:9]1[CH:10]=[C:2]([C:28]#[N:30])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Reactant: CC#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
A mixture of 5-bromo-7-chloro-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.349 g, 0.83 mmol), Pd(PPh3)4 (0.317 g, 0.25 mmol), sodium cyanide (0.048 g, 0.946 mmol), CuI (0.016 g, 0.086 mmol), acetonitrile (4 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (0.100 g, 33%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.32 (s, 2H), 4.79 (s, 2H), 7.20 (d, 2H), 7.35 (d, 2H), 7.58 (s, 1H), 7.70 (s, 1H). GC-MS: m/z 366 (M−1)+, 281 (M−85)+.
Reaction SMILES: [C:1](OC=O)(=[O:3])C.C(O)=O.C(OC(=O)C)(=O)C.[NH2:17][CH2:18][CH2:19][O:20][CH2:21][C:22]1[NH:23][C:24]([CH3:45])=[C:25]([C:41]([O:43][CH3:44])=[O:42])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[Cl:40])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[Cl:40][C:34]1[C:35]([Cl:39])=[CH:36][CH:37]=[CH:38][C:33]=1[CH:26]1[C:25]([C:41]([O:43][CH3:44])=[O:42])=[C:24]([CH3:45])[NH:23][C:22]([CH2:21][O:20][CH2:19][CH2:18][NH:17][CH:1]=[O:3])=[C:27]1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CC(=O)OC=O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOC(=O)C1=C(COCCNC=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Formic acetic anhydride (15 ml; prepared by heating a mixture of formic acid (5 ml) and acetic anhydride (10 ml) at 50°-60° C. for 1 hour) was added over 10 minutes to a stirred, ice-cooled solution of 2-(2-aminoethoxymethyl)-4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (4.4 g) in tetrahydrofuran (30 ml). The mixture was stirred at room temperature for 1.5 hours and then evaporated. The residue was dissolved in dichloromethane and the solution washed with 10% aqueous sodium carbonate solution, dried (Na2SO4), and evaporated. The residual solid was collected, washed with diethyl ether and dried to give the title compound as a hemihydrate (4.0 g), m.p. 178°-181° C. Found: C, 52.69; H, 5.05; N, 6.06. C21H24Cl2N2O6.0.5H2O requires C, 52.51; H, 5.25; N, 5.83%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:57][CH2:58][CH2:59][CH2:60]O.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Br:57][CH2:58][CH2:59][CH2:60][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:35][CH3:36])[N:27]=[CH:26][N:25]=[C:24]2[O:23][C:22]1[C:14]([F:13])=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:37])=[CH:16]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1O
Reactant: OCCCBr
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
Diethyl azodicarboxylate (0.847 g, 4.86 mmol) was added to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (1.5 g, 4.42 mmol), (prepared as described for the starting material in Example 1), triphenylphosphine (1.74 g, 6.63 mmol) and 3-bromo-1-propanol (0.923 g, 6.63 mol) in methylene chloride. After stirring for 1 hour at ambient temperature, triphenylphosphine (1.16 g) and DEAD (0.770 g) was added. After stirring for 30 minutes, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and ethyl acetate to give 6-(3-bromopropoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline (1.5 g, 73%).