Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.O>C(#N)C>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: c1ccc(C(c2ccccc2)N2CC(N3CCOCC3)C2)cc1
Temperature: 25 °C
Yield: 273 %

Procedure:
A solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (Preparation 1(b)) (24.46 g, 7.72 mmol), potassium carbonate (32 g, 3 mol equiv) and morpholine (7.34 ml, 1.09 mol equiv) in acetonitrile (200 ml) was heated under reflux for 4 hours. The solution was then cooled to room temperature, water (50 ml) added and the mixture concentrated in vacuo. The residue was then partitioned between ethyl acetate (400 ml) and water (400 ml) and the organic phase washed with water (2×400 ml). The organic phase was dried over MgSO4, and the solvent removed in vacuo. The residue was chromatographed using silica gel eluting with hexane:diethyl ether (1:1) to give the title compound (1 6.5 g).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH:18]([C:12]1[CH:17]=[CH:16][C:15]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)([CH3:20])[CH3:19]
Reactant: O=CC(=O)c1ccccc1
Reactant: CC(C)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(C)c1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and cumene (0.56 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 4 hours. Using the same procedure as in Example 1, 4'-iso-propylbenzoin was obtained as crystal (300.6 mg, 59.6% yield).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].O.C(OCC)C>O1CCCC1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[O:17][C:15]1[CH2:16][N:12]([C@@H:4]([CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:27])=[O:2])[C:13](=[O:26])[CH:14]=1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2c(F)cccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a stirred mixture of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (800 mg, 2.00 mmol) in tetrahydrofuran (10 mL) was added 0.5N lithium hydroxide solution (8.0 mL, 4.0 mmol). After addition was complete the mixture was stirred at 25° C. for 2 h. The reaction mixture was poured into water and diethyl ether and the layers were separated. The aqueous layer was made acidic with 1N aqueous hydrochloric acid and extracted with ethyl acetate (3×30 mL). The combined ethyl acetate fractions were washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to afford (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (740 mg, 97%) as a light brown solid: LR-ES-MS m/z calculated for C19H21ClFNO4 [M]+ 381, observed [M+H]+ 382.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:15]2[S:27][C:28]([CH3:30])=[CH:29][C:14]=2[C:13]=1O)=[O:11])[CH3:8]>CN(C=O)C>[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:15]2[S:27][C:28]([CH3:30])=[CH:29][C:14]=2[C:13]=1[Cl:4])=[O:11])[CH3:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1c(O)c2cc(C)sc2n(Cc2cccc(F)c2)c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cl)c2cc(C)sc2n(Cc2cccc(F)c2)c1=O
Temperature: 75 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
Oxalyl chloride (4.83 mL, 0.055 mol) was added to a solution of 7-(3-fluoro-benzyl)-4-hydroxy-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (69) (8 g, 0.022 mol) in DMF at −30° C. under argon. The temperature was raised gradually to 75° C. and stirred for 3 h. The solution was cooled and poured into ice water. The solids formed were filtered, washed by cold water and dried to yield 6.8 g (82%) of 4-chloro-7-(3-fluoro-benzyl)-2-methyl-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester. 1H-NMR (DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 2.45 (d, J=1.2 Hz, 3H), 4.33 (q, J=7.2 Hz, 2H), 5.31 (s, 2H), 7.05 (d, J=1.2 Hz, 1H), 7.09-7.17 (m, 3H), 7.40 (m, 1H) ppm, EIMS m/z 380 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19]O)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>C(#N)CC.O>[CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[CH:15]=[C:16]([CH2:19][N:49]3[CH2:48][CH2:47][N:46]([C:43]4[CH:42]=[CH:41][C:40]([Cl:39])=[CH:45][CH:44]=4)[CH2:51][CH2:50]3)[CH:17]=[N:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(Cc2ccccc2)c2ncc(CO)cc2N1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: O=C1CN(Cc2ccccc2)c2ncc(CN3CCN(c4ccc(Cl)cc4)CC3)cc2N1
Temperature: 90 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
4-benzyl-7-(hydroxymethyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (100 mg, 0.37 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (66.6 mg, 40%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 7.64 (d, J=1.8 Hz, 1H), 7.33 (d, J=4.5 Hz, 4H), 7.25-7.30 (m, 1H), 7.19-7.24 (m, 2H), 7.01 (d, J=1.8 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.72 (s, 2H), 3.86 (s, 2H), 3.36 (s, 2H), 3.07-3.15 (m, 4H), 2.44-2.49 (m, 4H). [M+H] calc'd for C25H26ClN5O, 448. found, 448.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1.C(OCC)C>O1CCOCC1>[ClH:1].[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1N
Reactant: Clc1nccc2ccccc12
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccccc1Nc1nccc2ccccc12
Product: Cl

Procedure:
1-Chloroisoquinoline (J. O. C. (1958), 23, 1071) (1.64 g, 0.01 mol) and o-toluidine (1.07 g, 0.01 mol) were heated together at reflux temperature in dry dioxan (20 ml) for 18 hours. After this time a light brown oil had precipitated in the hot solution. After cooling the mixture was evaporated to dryness to give an off-white, sticky solid. This was treated with diethyl ether (50 ml), collected, washed with ether and dried to give a white solid (2.07 g). This solid was crystallised from ethanol/ ether to give the title compound (1.97 g) as its hydrochloride salt, m.p. 229°-231°.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:11]3[CH2:12][CH2:13][C@:14]4([CH3:20])[C:18](=O)[CH2:17][CH2:16][C@H:15]4[C@@H:10]3[C@H:9](O)C[C@H:7]1[CH2:6][C@H:5]([OH:22])[CH2:4][CH2:3]2.C[C:24]([CH3:27])([O-:26])[CH3:25].[K+].O>O1CCCC1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH3:9]/[CH:10]=[C:15]1/[CH2:16][CH2:17][C@@H:18]2[C@:14]/1([CH3:20])[CH2:13][CH2:12][C@H:11]1[C@H:25]2[C@H:24]([OH:26])[CH2:27][C@H:7]2[C@:2]1([CH3:1])[CH2:3][CH2:4][C@@H:5]([OH:22])[CH2:6]2
Reactant: CC(C)(C)[O-]
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1C[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C/C=C1/CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 72 h
Yield: 82 %

Procedure:
A solution of 1.282 g (ca. 0.0034 mol) of 3α,5β,7α-3,7-dihydroxyandrostan-17-one in 5 ml of tetrahydrofuran was added to a room temperature solution of 113 ml of tetrahydrofuran, 1.875 g (0.0167 mol) of potassium t-butoxide and 6.215 g (0.0167 mol) of ethyltriphenylphosphonium bromide. The mixture was stirred under argon for 72 hr. and then was poured into 750 ml of water containing 250 g of ice. After 30 min., the mixture was collected by suction filtration and washed with water. The dried, crude material (3.0 g) was chromatographed on 200 g of silica gel to afford, on elution with ethyl acetate--hexane (2:1), 0.888 g of material (82%). Trace amounts of impurities were removed by dissolving in a mixture of hexane and methylene chloride. The methylene chloride was distilled, the mixture was cooled, and the solid product, (Z)-3α,5β,7α-pregn-17(20)-ene-3,7-diol, was collected by filtration. The analytical sample was recrystallized from ethyl acetate then acetonitrile, mp 160°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([N+:18]([O-])=O)[C:11]=2[N:10]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=2[N:10]=1
Reactant: COc1ccccc1-c1nc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1nc2c(N)cccc2[nH]1
Yield: 95.2 %

Procedure:
A suspension of 163 (0.620 g, 2.303 mmol), ammonium chloride (0.105 g, 1.957 mmol) and iron (0.643 g, 11.51 mmol) in ethanol (20 ml) and water (4.00 ml) was heated at reflux for 2 hours. The reaction mixture was cooled and filtered through Celite and the filtrate was taken to dryness, H20 was added and the material extracted with ethyl acetate. The EtOAc extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give crude 164 (0.5245 g, 2.192 mmol, 95% yield) as brown solid. LRMS (ESI): (calc.) 239.3 (found) 240.2 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31](S(C)=O)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1>C1COCC1>[CH:20]1([NH:23][C:24]([C:26]2[S:39][C:29]3=[N:30][C:31]([O:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]4)=[C:32]([Cl:35])[C:33]([CH3:34])=[C:28]3[C:27]=2[NH2:40])=[O:25])[CH2:22][CH2:21]1
Reactant: OCCN1CCNCC1
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(Cl)c(OCCN2CCNCC2)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
To a solution of 1-(2-hydroxyethyl)piperazine (1.061 g, 8.15 mmol) in THF (3 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes)(3.50 ml, 3.50 mmol). The reaction mixture is stirred for 15 minutes and then is treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (0.345 g, 1.00 mmol). The reaction mixture is heated at 75° C. for 1 hour, cooled to room temperature, and then quenched by the addition of water (15 ml). Ice is added to the reaction mixture and, while stirring, a yellow precipitate is formed. This solid is collected by filtration and placed in the vacuum oven to dry (60° C. for 16 hours). This affords the title compound as a yellow solid (0.245 g, 71%). Mass (m/z): 410.2 (M++1), 408.2 (M+−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[O:17][CH3:18])[CH2:9][CH2:8]1)[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[O:17][CH3:18])[CH2:9][CH2:8]1)[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC1(c2cccc(F)c2OC)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)(CC1(c2cccc(F)c2OC)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
9.6 g (34.3 mmol) of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-oxopropionate and 34.5 ml (233 mmol) of (trifluoromethyl)-trimethylsilane in 343 ml of DMF are mixed with 46.9 g of cesium carbonate at 0° C. It is stirred for 2 hours at 0° C. and then the reaction solution is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-40%), 10.4 g of ethyl-3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-hydroxy-2-(trifluoromethyl)-propionate is obtained as a yellow oil. This oil is mixed in 297 ml of diethyl ether at 0° C. with 2.25 g (59.4 mmol) of lithium aluminum hydride and stirred for one more hour at room temperature. 20 ml of saturated ammonium chloride solution is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is extracted several times with diethyl ether, washed with saturated sodium chloride solution, dried with sodium sulfate, and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-50%), 5.6 g of 3-[1-(3-fluoro-2-methoxyphenyl)-cyclopropyl]-2-(trifluoromethyl)-propane-1,2-diol is obtained. 12.4 ml (89 mmol) of triethylamine and, in portions over 10 minutes, 11 g (70 mmol) of pyridine/SO3 complex are added to 5.6 g (18.1 mmol) of diol in 100 ml of dichloromethane and 61 ml of DMSO. It is stirred over 3 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and after chromatographic purification on silica gel (hexane/ethyl acetate, 0-50%), 5.9 g of product is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)O1>>[O:18]1[CH2:19][CH2:20][N:15]([C:4]2[C:5]3[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[S:8][C:6]=3[N:7]=[C:2]([C:29]3[CH:30]=[C:31]4[CH:37]=[CH:36][NH:35][C:32]4=[N:33][CH:34]=3)[N:3]=2)[CH2:16][CH2:17]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CC(C)(O)c1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: CC(C)(O)c1cc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc2s1

Procedure:
2-(2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)propan-2-ol (100) mg was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine via General Procedure A to give 120 mg of 351 following reverse phase HPLC purification. MS (Q1) 396.2 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[N:6]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:5]2=[O:53].[CH:54]([N:57]=[C:58]=[O:59])([CH3:56])[CH3:55]>C(Cl)Cl.CCOC(C)=O>[CH2:12]([C:7]1[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=2)[C:5](=[O:53])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:58](=[O:59])[NH:57][CH:54]([CH3:56])[CH3:55])[CH:3]=2)[N:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)N=C=O
Reactant: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)NC(C)C)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 72 h
Yield: 70 %

Procedure:
To solution of 0.069 g (0.1 mmol) of the aminoquinazolinone from Example 40 in 1 mL of CH2Cl2 was added 12.7 mg (0.15 mmol) of isopropylisocyanate. The reaction mixture was stirred for 3 days. The mixture was diluted with 20 mL of EtOAc, washed with water (2×5 mL), brine (1×5 mL) and dried over MgSO4. The mixture was filtered and concentrated in vacuo and the residue was purified by MPLC over a silica Lobar B column eluting with 50% EtOAc/hexanes to give 59.5 mg (0.07 mmol) of an oil, 76% yield. 1H-NMR (CDCl3 300 MHz): 0.86 (t, 3H, J=7.3 Hz), 1.07 (d, 6H, J=6.5 Hz), 1.29 (m, 2H), 1.68 (m, 2H), 2.59 (3 line m, 2H, J=7.06 Hz), 3.95 (m, 1H), 5.18 (d, 1H,J=7.7 Hz), 5.28 (bs, 2H), 7.12 (m, 6H), 7.07 (d, 2H), 7.19-7.32 (m, 11H), 7.43 (m, 2H), 7.57 (m, 2H), 7.90 (m, 2H), 8.13 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([NH2:15])(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[N:16]=NC1C=CC(Cl)=CC=1>Cl>[NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12]([NH2:15])(=[O:13])=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:16]
Reactant: Nc1c(N=Nc2ccc(Cl)cc2)ccc2c(S(N)(=O)=O)cccc12
Agent: Cl
Product: Nc1ccc2c(S(N)(=O)=O)cccc2c1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
To a solution of 18,1 g (SO mmol) stannous chloride dihydrate in 100 ml concentrated hydrochloric acid was added 10,0 g (27,7 mmol) 1-amino-2-(4-chlorophenylazo)-naphthalene-5-sulphonamide. The mixture was stirred at 70° C. for 3 h. After cooling to 25° C., the mixture was poured into 200 ml ice-water. The precipitate was filtered off and washed with 4N hydrochloric acid. The crude product was stirred with ice-water The precipitate was filtered off and washed with ice-water and ethanol to give 6,7 g 1,2-diamino-naphthalene-5-sulphonamide as a hydrochloride salt.
Reaction SMILES: [C:1]1([C:12]([OH:14])=O)[CH:2]=[CH:3][CH:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]2[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=2[CH:60]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:48][C:44]1[CH:43]=[C:42]([CH:40]([OH:41])[CH:39]([NH:38][C:12]([C:1]2[CH:2]=[CH:3][CH:4]=[C:5]3[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=23)=[O:14])[CH2:49][C:50]2[CH:51]=[CH:52][C:53]3[O:57][CH2:56][C:55]([CH3:59])([CH3:58])[C:54]=3[CH:60]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: CC1(C)COc2ccc(CC(N)C(O)c3cccc(Cl)c3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)COc2ccc(CC(NC(=O)c3cccc4c3C=CCCC4)C(O)c3cccc(Cl)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (239 mg, 1.27 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (243 mg, 1.27 mmol) and 1-hydroxybenzotriazole monohydrate (195 mg, 1.27 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1-propanol (0.40 g, 1.21 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)methyl]-2-hydroxyethyl}-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (326 mg, 54%) as colorless crystals.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[NH:22][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C@@:15]21[CH2:33][C:25]1=[N:26][CH:27]=[C:28]([C:30](O)=[O:31])[CH:29]=[C:24]1[CH2:23]2.Cl.[NH2:35][C@H:36]1[CH2:41][C@@H:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[CH3:48])[C@@H:39]([CH3:49])[N:38]([CH2:50][C:51]([F:54])([F:53])[F:52])[C:37]1=[O:55].N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>CN(C=O)C>[CH3:49][C@H:39]1[N:38]([CH2:50][C:51]([F:53])([F:54])[F:52])[C:37](=[O:55])[C@@H:36]([NH:35][C:30]([C:28]2[CH:29]=[C:24]3[CH2:23][C@@:15]4([C:16]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:22][C:14]4=[O:13])[CH2:33][C:25]3=[N:26][CH:27]=2)=[O:31])[CH2:41][C@H:40]1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH3:48]
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: Cc1ccccc1[C@@H]1C[C@H](N)C(=O)N(CC(F)(F)F)[C@@H]1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1[C@@H]1C[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)N(CC(F)(F)F)[C@@H]1C
Temperature: 23 °C
Reaction time: 18 h

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.10 g, 0.53 mmol) was added to a solution of (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 1) (111 mg, 0.39 mmol), (3S,5S,6R)-3-amino-6-methyl-5-(2-methylphenyl)-1-(2,2,2-trifluoroethyl)piperidin-2-one hydrochloride (described in Intermediate 6) (127 mg, 0.38 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (HOAt, 15 mg, 0.11 mmol), and triethylamine (0.16 mL, 0.91 mmol) in DMF (3 mL), and the resulting mixture was stirred at 23° C. for 18 h. The reaction mixture was then partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 1% methanol→7% methanol/dichloromethane to afford the title compound. HRMS: m/z=564.2219 (M+1), calculated m/z=564.2234 for C30H28F3N5O3. 1H NMR (500 MHz, CDCl3) δ 8.91 (s, 1H), 8.56 (s, 1H), 8.17 (dd, 1H, J=5.0, 1.5 Hz), 8.05 (s, 1H), 7.30 (d, 1H, J=5.0 Hz), 7.20 (m, 3H), 7.12 (m, 2H), 6.89 (dd, 1H, J=7.5, 5.0 Hz), 5.00-4.94 (m, 1H), 4.55 (m, 1H), 3.93-3.90 (m, 1H), 3.81-3.76 (m, 2H), 3.68 (d, 1H, J=16.5 Hz), 3.31-3.23 (m, 2H), 3.17 (d, 1H, J=16.5 Hz), 2.75-2.67 (m, 2H), 2.41 (s, 3H), 1.11 (d, 3H, J=6.5 Hz).