Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:27]3[CH:28]=[N:29][C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([N:15](C(=O)C)[C:16](=[O:18])[CH3:17])[O:12]2)=[CH:7][CH:6]=1)(=O)C.O.NN>C(O)C>[C:16]([NH:15][C:11]1[O:12][C:13]2[C:8]([CH:9]([C:27]3[CH:28]=[N:29][C:30]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:6]=[C:5]([OH:4])[CH:14]=2)(=[O:18])[CH3:17]
Reactant: CCOC(=O)C1=C(N(C(C)=O)C(C)=O)Oc2cc(OC(C)=O)ccc2C1c1cnc2ccccc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(NC(C)=O)Oc2cc(O)ccc2C1c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
Ethyl 7-(acetyloxy)-2-(diacetylamino)-4-quinolin-3-yl-4H-chromene-3-carboxylate (268 mg, 0.55 mmol) was dissolved in absolute ethanol (1.7 mL). Hydrazine hydrate (35 μL, 0.72 mmol) was added and the mixture stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness. 1H NMR analysis showed incomplete conversion of the starting material. The product was suspended in absolute ethanol (1.7 mL) and hydrazine hydrate (35 μL, 0.72 mmol) added. The mixture was stirred at room temperature for 2 h. The mixture was filtered. The residue was washed with ethanol (1.0 mL) and ethyl acetate (2.0 mL). The residue was dissolved in boiling ethanol (16 mL) and the volume reduced to half by heating under a stream of nitrogen. The mixture was cooled to 4° C. and filtered. The residue was dried at the pump to give the title compound (65 mg, 29% yield) as pale yellow needles.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(C)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: COCCCN
Reactant: CCCCCBr
Solvent: CC(C)O
Product: CCCCCNCCCOC
Temperature: 90 °C
Yield: 49 %

Procedure:
891 g (10 moles) of 3-methoxypropylamine are mixed with one liter of isopropanol at ambient temperature in a reactor. 755 g (5 moles) of n-pentyl bromide are added to the solution and then heated under reflux (about 90° C.) for 12 hours. The solvent is evaporated at a reduced pressure, the residue diluted with two liters of 2N sodium carbonate, a supernatent oil is separated and distilled at reduced pressure, the 104°-8° C./20 mmHg fraction being collected. Thus 390 g of product are obtained. Yield 73%.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][N:14]2[N:16]=[C:17]([I:24])[C:18]([C:19]([O:21]CC)=[O:20])=[C:13]2[CH2:12][N:11]1[C:25](=[O:35])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=1)(C(C)(C)C)(C)C.[Li+].[OH-]>C1COCC1.O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:25]([N:11]2[CH:10]([CH2:9][OH:8])[CH2:15][N:14]3[N:16]=[C:17]([I:24])[C:18]([C:19]([OH:21])=[O:20])=[C:13]3[CH2:12]2)=[O:35])=[CH:32][CH:31]=1)#[N:34]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)Nc1ccc(C#N)cc1)C(CO[Si](C)(C)C(C)(C)C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(NC(=O)N2Cc3c(C(=O)O)c(I)nn3CC2CO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
To a solution of Intermediate 351E (0.7 g, 1.148 mmol) in THF (10 mL) and water (5 ml) was added LiOH (0.083 g, 3.45 mmol) and the reaction mass was stirred at RT for 24 h. The volatiles were evaporated; the residue was diluted with water (10 mL) and neutralized with an aqueous solution of 1.0 N HCl. The solid product separated was filtered and dried to afford Intermediate 351F (0.4 g, 74%) as an off-white solid which was taken to the next step without further purification. MS(ES): m/z=468 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 12.35-12.80 (br, 1H), 9.33 (s, 1H), 7.69-7.74 (m, 2H), 7.62-7.68 (m, 2H), 5.20-5.30 (m, 1H), 5.10-5.19 (m, 1H), 4.72 (d, J=4.53 Hz, 1H), 4.46 (d, J=18.51 Hz, 1H), 4.27-4.38 (m, 2H), 3.40-3.48 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:5]=1[NH:6][CH2:7][CH:8]=[O:9])[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[Cl:27][CH2:28][C:29]([N:6]([CH2:7][CH:8]=[O:9])[C:5]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:30]
Reactant: O=C(Cl)CCl
Reactant: CCCc1ccc(F)cc1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCCc1ccc(F)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-propyl-5-fluoroanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a tenperature of about 0°C and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-propyl-5-fluoroanilino)acetaldehyde.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1CC=CCC=1>[Pd]>[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([N:8]2[CH2:11][CH:10]([C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]4)=[CH:19][CH:20]=3)=[O:13])[CH2:9]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CN(c4ccc(Cl)nn4)C3)cc2)CC1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CN(c4cccnn4)C3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask was added tert-butyl 4-(4-(1-(6-chloropyridazin-3-yl)azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate (550 mg, 1.165 mmol) and Pd/C (93 mg, 0.087 mmol). The flask was flushed with nitrogen for 10 minutes and ethanol (11.7 ml) was added. Triethylamine (0.162 ml, 1.165 mmol) and cyclohexa-1,4-diene (654 mg, 8.16 mmol) were added and the reaction was stirred at 80° C. for 1 hour, cooled and filtered through diatomaceous earth. The filtrate was concentrated in vacuo and the residue was purified by regular phase flash column chromatography to give the title compound.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.[NH:9]1[CH2:13][CH2:12][C:11]2([N:18]3[CH:19]=[N:20][CH:21]=[C:17]3[CH2:16][CH2:15][CH2:14]2)[CH2:10]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[O:1]1[C:5]([C:6]([N:9]2[CH2:13][CH2:12][C:11]3([N:18]4[CH:19]=[N:20][CH:21]=[C:17]4[CH2:16][CH2:15][CH2:14]3)[CH2:10]2)=[O:8])=[CH:4][N:3]=[CH:2]1
Reactant: c1ncn2c1CCCC21CCNC1
Reactant: O=C(O)c1cnco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cnco1)N1CCC2(CCCc3cncn32)C1
Temperature: 25 °C

Procedure:
1.5 mmol of oxazole-5-carboxylic acid [118994-90-4] are dissolved in 5 ml of dichloro-methane and the solution is admixed at 0° C. with 1.6 mmol of chlorenamine. The reaction solution is subsequently stirred at room temperature for an hour and then added dropwise at 0° C. to a solution of 1 mmol of 7,8-dihydro-6H-spiro[imidazo[1,5-a]pyridine-5,3′-pyrrolidine] (Example 3a) and 2 mmol of triethylamine in 5 ml of dichloromethane. The reaction mixture is subsequently stirred at room temperature for 3 hours, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane (3×). The combined organic extracts are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH2:57]([S:59][CH2:60][CH2:61][NH2:62])[CH3:58]>CN(C=O)C>[CH2:57]([S:59][CH2:60][CH2:61][NH:62][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:31])[CH3:58]
Reactant: CCSCCN
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCSCCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol), HOBt (32 mg, 1.2 eq.), EDAC.HCl (45 mg, 1.2 eq.), TEA (0.138 mL, 5 eq.) and 2-ethylsulfanyl-ethylamine hydrochloride salt (69 mg, 2.5 eq.) in DMF (2 mL) was stirred at rt for 7 days. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, dried, concentrated and purified on a silica gel column to give the titled compound as a yellow waxy solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]3[N:12](C(=O)C(F)(F)F)[CH2:11][CH:10]([CH2:25][Cl:26])[C:9]=3[C:8]=2[CH:27]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].O>CO.C(Cl)Cl>[ClH:26].[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]3[NH:12][CH2:11][CH:10]([CH2:25][Cl:26])[C:9]=3[C:8]=2[CH:27]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Product: Cl
Reaction time: 1 h
Yield: 202.5 %

Procedure:
A solution of 175 (45 mg, 0.11 mmol) and Cs2CO3 (38 mg, 0.11 mmol) in MeOH (3 mL) and CH2Cl2 (6 mL) was stirred for 15 min. Water w added and the mixture was extracted with EtOAc (×3). The combined EtOAc extras were washed with water (×2), brine (×3), dried, and evaporated. The residue was dissolved in HCl(g) saturated dioxane (5 mL) and stirred for 1 h. The dioxane was evaporated to give 8-acetyl-1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole hydrochloride (176) (38 mg, 100%): mp>300° C.; 1H NMR [(CID3)2SO] (two H not observed) 8.42 (d, J=1.3 Hz, 1 H), 8.19 (d, J=9.1 Hz, 1H), 7.80 (dd, J=9.1, 1.7 Hz, 1H), 7.77 (s, 1H), 4.41-4.33 (m, 1H), 3.96 (dd, J=11.0, 4.1 Hz, 1H), 3.85 (t, J=10.1 Hz, 1H), 3.77 (dd, J=11.0, 2.6 Hz, 1H), 3.73 (dd, J=10.3, 2.7 Hz, 1H), 2.74 (s, 3H); 13C NMR δ 197.9, 150.0, 147.1, 135.3, 130.0, 127.1, 124.3, 123.6, 121.6, 119.8, 111.0, 50.8, 46.6, 42.7, 26.8. This material was used directly in the next step.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([CH3:23])[N:16]=1.[C:24](=[O:26])=[O:25]>O1CCCC1.O>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([CH2:23][C:24]([OH:26])=[O:25])[N:18]=1
Reactant: O=C=O
Reactant: COc1cc(OC)nc(C)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(OC)nc(CC(=O)O)n1
Reaction time: 0.33 h

Procedure:
n-Butyllithium (200 ml of 2N in pentane) was added dropwise over 30 minutes to a stirred solution of di-isopropylamine (40.4 g) in tetrahydrofuran (200 ml) at -70° C. under nitrogen. The mixture was stirred for 20 minutes and then 4,6-dimethoxy-2-methylpyrimidine (61.6 g) in tetrahydrofuran (200 ml) was added dropwise over 20 minutes. The mixture was stirred at -70° C. for 30 minutes before being poured onto a large excess of solid carbon dioxide. The mixture was allowed to warm to room temperature before water (800 ml) was added. The clear solution was concentrated to half volume under vacuum and was then washed with ether. The aqueous phase was acidified with concentrated hydrochloric acid and the resulting solid was filtered, washed with water and dried to give 58.3 g of (4,6-dimethoxypyrimidin-2-yl)acetic acid.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(Cl)(O[C:33](=[O:39])OC(Cl)(Cl)Cl)Cl.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>O1CCCC1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:33]([N:45]4[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]4)=[O:39])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1
Temperature: 80 °C
Yield: 118.3 %

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.25 g, 0.9 mmol) was dissolved in tetrahydrofuran (10 mL) and triethylamine (0.138 mL, 1.0 mmol) was added. At 0° C. triphosgene (121 mg, 0.4 mmol) was added and the reaction mixture subsequently heated to 80° C. for 3 h. Upon cooling to ambient temperature triethylamine (0.138 mL, 1.0 mmol) and 1-methyl-piperazine (0.1 mL, 0.9 mmol) were added and the whole reaction mixture was stirred over night at 50° C. After evaporation of the solvent, the residue was taken up in water and extracted with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and the filtrate was evaporated. The residue was taken up in a small amount of ethyl acetate, sonicated and kept over night in a refrigerator whereby a crystalline precipitate formed. The precipitate was isolated and dried on vacuum to yield the title compound (190 mg; 52%) as an off-white solid; MS: m/e=402.6 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(O)(C)C.CCCCCC>C(O)CCC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[C:3]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)c1cc2c(Cl)ncnc2[nH]1
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: CCCCO
Product: CCOC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 29.0 g (128 mmol) of 4-chloro-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine and 18.0 ml (171 mmol) of 3-chloro-aniline in 430 ml of n-butanol are stirred at 100° C. for 3 hours (almost dissolved after ≈1 hour, then a thick suspension forms). The reaction mixture is cooled to ~50° C., then 400 ml of isopropanol/hexane (1:1) are added thereto. The reaction mixture is then cooled to RT and the product is filtered off and washed with isopropanol and hexane. Stirring from diethyl ether yields the title compound: 1H-NMR (DMSO-d6) 13.0 and 10.53 (2 sb, 2HN), 8.48 (s, 1H), 8.13 (m, 1H), 7.78 (dm, J=8, 1H), 7.76 (s, 1H), 7.45 (t, J=8, 1H), 7.21 (dm, J=8, 1H), 4.37 (q, J=7, 2H), 1.37 (t, J=7, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22]C(=O)OCCCC)=[O:9])=[CH:4][CH:3]=1.[CH2:30]([NH:32][C:33]([N:35]1[C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36]1)=[O:34])[CH3:31].CCN(CC)CC>CS(C)=O>[NH2:22][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:16][C:11]=1[NH:10][C:8]([C:5]1[CH:4]=[CH:3][C:2]([N:42]2[CH2:41][CH2:40][C:39]3([N:35]([C:33]([NH:32][CH2:30][CH3:31])=[O:34])[CH2:36][CH2:37][CH2:38]3)[CH2:44][CH2:43]2)=[N:7][CH:6]=1)=[O:9]
Reactant: CCNC(=O)N1CCCC12CCNCC2
Reactant: CCCCOC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)N1CCCC12CCN(c1ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cn1)CC2
Reaction time: 1 h

Procedure:
A solution of intermediate F (82 mg, 0.19 mmol), N-ethyl-1,8-diazaspiro[4.5]-decane-1-carboxamide (73 mg, 0.35 mmol), and NEt3 (43 μL, 0.31 mmol) in 5 mL of DMSO was stirred at 90° C. for 12 h. The reaction mixture was partitioned between EtOAc and saturated NaHCO3, the organic layer was dried (MgSO4), filtered and concentrated. The residue was stirred in 2 mL of TFA and 2 mL of CH2Cl2 for 1 h at room temperature and concentrated. Reverse-phase chromatography (10 to 100% MeCN/water with 0.05% TFA) followed by neutralization with EtOAc/saturated NaHCO3 extraction and drying with MgSO4 gave the title compound: MS (ESI+): cal'd [M+H]+ 505.2, obs'd 505.2.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][C:26]1[CH:28]=[CH:29][C:23]([OH:22])=[CH:24][C:25]=1[CH3:30])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(O)ccc1N
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccc(O)cc1C
Yield: 44.8 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (2.48 g, 6.63 mmol) and 4-hydroxy-2-methylaniline (1.06 g, 8.62 mmol) in acetonitrile (20 ml) was refluxed for 8 h. The reaction mixture was evaporated and the residue was chromatographed (SiO2 ; CH2Cl2 : MeOH 95:5) yielding 1.22 g (45%) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:21]1[O:22][C:23]2[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=2)[N:25]=1>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[O:22][C:23]3[C:24](=[C:26]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][CH:29]=3)[N:25]=2)[CH2:10][C@@H:9]1[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-(2S)-2-isobutylpiperazine (384 mg, 1.6 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography ((silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(3S)-3-isobutylpiperazine-1-yl)benzoxazole-4-carboxylate (219 mg, 32%) as a clear oil: 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([N:19]1[CH2:24][CH2:23][NH:22][C@@H:21]([CH3:25])[CH2:20]1)C1C=CC=CC=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[CH2:23][CH2:24][NH:19][CH2:20][C@@H:21]2[CH3:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: C[C@H]1CN(Cc2ccccc2)CCN1
Reactant: Clc1cc(Br)c2occc2c1
Product: C[C@H]1CNCCN1c1cc(Cl)cc2ccoc12
Product: Cl

Procedure:
Beginning with 5-chloro-7-bromobenzofuran and 1-benzyl-3(S)-methylpiperazine, the title compound was prepared as described.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.[O:18]=[C:19]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([C:28]#[N:29])=[CH:24][CH:25]=2)[NH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[ClH:1].[CH:12]([N:11]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9][O:8][C:4]1[N:5]=[CH:6][N:7]=[C:2]([C:27]2[C:26]3[C:21](=[CH:22][C:23]([C:28]#[N:29])=[CH:24][CH:25]=3)[NH:20][C:19]=2[OH:18])[CH:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)N(CCOc1cc(Cl)ncn1)C(C)C
Reactant: N#Cc1ccc2c(c1)NC(=O)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)N(CCOc1cc(-c2c(O)[nH]c3cc(C#N)ccc23)ncn1)C(C)C
Product: Cl

Procedure:
The title compound was prepared as described for Example 120 using N-{2-[(6-chloropyrimidin-4-yl)oxy]ethyl}-N-isopropylpropan-2-amine (0.10 g, 0.39 mmol), 2-oxoindoline-6-carbonitrile (0.074 g, 0.47 mmol) and cesium carbonate (0.50 g, 1.54 mmol). Yield 0.026 g, 15%: 1H NMR (CD3OD, 400 MHz) δ 8.59 (s, 1H), 7.81 (d, J=8 Hz, 1H), 7.55 (d, J=1 Hz, 1H), 7.45 (dd, J=8, 1 Hz, 1H), 6.64 (s, 1H), 4.40 (t, J=6 Hz, 1H), 3.87 (m, 1H), 3.58 (t, J=6 Hz, 1H), 1.44 (m, 3H); MS (ESP) m/z 380 (M++1).
Reaction SMILES: [N:1]1([CH:5]2[CH2:10][CH2:9][CH:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH:5]2[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N2CCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(N2CCC2)CC1

Procedure:
tert-butyl N-[4-(azetidin-1-yl)cyclohexyl]carbamate (Intermediate 227; 260 mg, 1.01 mmol) was taken up in DCM (3 mL) and TFA (2 mL) and stirred at ambient temperature for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1.CC(O)=[O:35].O.OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[CH:16][C:17]3[CH:18]=[C:19]([OH:35])[CH:20]=[CH:21][CH:22]=3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:32]=1
Reactant: CC(=O)O
Reactant: CC1(C)OB(c2cccc(C=C3c4ccc(Cl)cc4CCc4cccnc43)c2)OC1(C)C
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: Oc1cccc(C=C2c3ccc(Cl)cc3CCc3cccnc32)c1

Procedure:
Mix 8-chloro-11-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (300 mg, 0.68 mmol), HOAc (1 mL), water (1 mL), THF (5 mL) and 30% H2O2 (mL). Stir the reaction at RT for 4 h. Quench with aqueous Na2S2O3 and extract the product into EtOAc. Dry (MgSO4) and concentrate to give 250 mg crude product. Purify by column chromatography (15% ethyl acetate/hexane) to give 66 mg 3-(8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidenemethyl)-phenol, Z-isomer as a white solid, mp 221.2° C. MS (ES) 334 (M+1), 332 (M−1). HPLC shows 99% purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5]([C:19](O)=[O:20])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1.[CH3:23][C:24]([C:27]([O:29][CH3:30])=[O:28])([CH3:26])[NH2:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5]([C:19]([NH:25][C:24]([CH3:26])([C:27]([O:29][CH3:30])=[O:28])[CH3:23])=[O:20])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:8]=1
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)O)c1=O
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)NC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(OC)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.1 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylic acid (300 mg), methyl 2-methylalaninate (134 mg), HOBt (219 mg), WSC (275 mg) and N,N-diisopropylethylamine (0.834 mL) in THF (3.18 mL) was stirred at room temperature for 17 hr, and water was added. The precipitate was collected by filtration, and washed with water and hexane to give the title compound (336 mg).