Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1.[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=2[F:28])[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:19]=1[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:14][C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[N:21]=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:19]=2[CH3:36])[C:5]([C:8]2[CH2:9][CH2:10][O:11][CH2:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1C1=CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1C1=CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinamine (0.17 g, 0.67 mmol) in dry DMF (5.0 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (54.9 mg, 1.37 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(2-pyridinyl)quinoline (0.22 g, 0.74 mmol) was added in portions. Upon complete addition, the mixture was warmed to 60° C. After 18 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted five times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the brownish residue was treated with isopropanol and warmed to 45° C. After 30 min, the solid was filtered and rinsed twice with MeOH to afford a tan solid as mostly N-(5-bromo-2-(3,6-dihydro-2H-pyran-4-yl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:36]1[NH:37][C:38]2[CH:39]=[CH:40][CH:41]=[C:42]3[C:48](=[O:49])[NH:47][CH2:46][CH2:45][C:44]=1[C:43]=23.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:11][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:36]1[NH:37][C:38]2[CH:39]=[CH:40][CH:41]=[C:42]3[C:48](=[O:49])[NH:47][CH2:46][CH2:45][C:44]=1[C:43]=23
Reactant: OCCCc1ccccc1Br
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: O=C1NCCc2c(-c3ccccc3CCCO)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Example YY, 3-(2-bromo-phenyl)-propan-1-ol (215 mg, 1.00 mmol), diboron pinacol ester (279 mg, 1.10 mmol), 1,1′-bis(diphenyl phosphino) ferrocene dichloropalladium (24 mg, 0.03 mmol), and potassium acetate (294 mg, 3.00 mmol), 2-Bromo-3,4,5,6-tetrahydro-azepino[5,4,3-cd]indol-6-one (239 mg, 0.90 mmol), a second portion of 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (24 mg, 0.03 mmol), and sodium carbonate (2.5 mL of a 2.0 M aqueous solution, 5.00 mmol) were reacted to yield 2-[2-(3-hydroxy-propyl)-phenyl]-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 127 mg (44%) as a beige solid: m.p. 233.5-234.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 1.53 (m, 2H), 2.61 (t, J=7.8 Hz, 2H), 2.69 (m, 2H), 3.23 (ABq, J=6.6, 5.1 Hz, 2H), 3.37 (m, 2H), 4.39 (t, J=5.1 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.35 (m, 4H), 7.51 (dd, J=7.8, 0.9 Hz, 1H), 7.70 (dd, J=7.5, 0.9 Hz, 1H), 8.03 (br t, 1H), 11.39 (br s, 1H). MS (FAB, MH+): 321. Anal. (C20H20N2O2.0.1 CH2Cl2) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[CH:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Reactant: ClCc1cccnc1
Agent: Cl
Product: COc1ccc(C2=NN(Cc3cccnc3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and 3-picolylchloride hydrochloride as described for compound 105. Purified by chromatography (ethyl acetate). Crystallized from diethyl ether. M.p. 117°-120° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@:7]1([C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[O:20][CH:21]2O)[C@H:16]([Cl:31])[C@H:15]3[OH:32])[CH2:12][CH2:11]1)[C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4].C(=O)([O-])O.[Na+].Cl>O.CO.O1CCCC1>[C:3]([O:6][C@:7]1([C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[O:20][CH2:21]2)[C@H:16]([Cl:31])[C@H:15]3[OH:32])[CH2:12][CH2:11]1)[C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC(O)[C@]4(C)[C@H]3CC[C@@]21C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Sodium borohydride (64 mg) was added to a mixture of 170 mg of 17α-acetoxy-6β-chloro-1ξ,7α-dihydroxy-2-oxa-4-pregnene-3,20-dione, 62 mg of sodium hydrogen carbonate, 4 ml of tetrahydrofuran, 9.2 ml of methanol and 8.2 ml of water. The reaction mixture was stirred at room temperature for 30 minutes, and 4 ml of 50% hydrochloric acid was added. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by TLC [developing solvent: chloroform/acetone (9/1)] to give 154 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione. The 1H NMR spectrum of this compound was the same as that of the compound produced in Example 18.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:41]=[CH:40][C:29]([O:30][C:31]([CH3:39])([CH3:38])[CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:28][CH:27]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:27]=[CH:28][C:29]([O:30][C:31]([CH3:39])([CH3:38])[CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:40][CH:41]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: CC(C)(CN1CCCC1)Oc1ccc(Br)cc1
Product: CC(C)(CN1CCCC1)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 1 using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 1-(2-(4-bromophenoxy)-2-methylpropyl)pyrrolidine.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]O.[CH3:7][C:8]([C:11]1[N:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][N:12]=1)([CH3:10])[CH3:9]>>[CH3:10][C:8]([C:11]1[N:12]=[CH:13][C:14]([CH2:17][C:18]([O:20][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])=[O:19])=[CH:15][N:16]=1)([CH3:7])[CH3:9]
Reactant: CC(C)=CCO
Reactant: CC(C)(C)c1ncc(CC(=O)O)cn1
Product: CC(C)=CCOC(=O)Cc1cnc(C(C)(C)C)nc1

Procedure:
Prepared according to the esterification process described in Example 19, Method 1 from 3-methylbut-2-en-1-ol and 2-[2-(1,1-dimethylethyl)pyrimidin-5-yl]acetic acid
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[N:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[C:3]1=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(O)CCC>C(N(CC)CC)C>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[N:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][N:25]2[CH2:24][CH2:23][N:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=3)[CH2:27][CH2:26]2)[C:3]1=[O:14]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cn1c(=O)cnn(CCCCCl)c1=O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)cnn(CCCCN2CCN(c3cccc(Cl)c3)CC2)c1=O
Yield: 44.9 %

Procedure:
The compound 4c (5.5 g; 0.025 mol) and 4-(3-chlorophenyl)piperazine (9.83 g; 0.05 mol) are heated for 3 hours in refluxing butanol (150 ml) in the presence of triethylamine (10 ml). The mixture is concentrated to dryness under vacuum, taken up in water and then extracted with ethyl ether (2×50 ml). The dried organic phases (Na2SO4) are concentrated to dryness under vacuum to give an oil which crystallizes from isopropyl ether (70 ml). After recrystallization from 2-propanol and drying under vacuum at 40° C., the compound 4 (4.24 g) is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:21]([BH3-])#[N:22].[Na+].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>C(O)(=O)C.CO>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH3:15][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([CH2:1][NH:22][CH3:21])[CH:4]=2)[N:14]=1
Reactant: Cc1ccc(C#N)c(Oc2cccc(C=O)c2)n1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2nc(C)ccc2C#N)c1
Yield: 56.8 %

Procedure:
2-(3-Formyl-phenoxy)-6-methyl-nicotinonitrile (0.77 g, 3.2 mmol), methylamine (2M in methanol, 7.0 mL, 14 mmol) and sodium cyanoborohydride (250 mg, 4.0 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (100 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.36 g, 3.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 6-methyl-2-(3-methylaminomethyl-phenoxy)-nicotinonitrile fumarate (650 mg, 55%) as an off-white solid.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.C([Li])CCC.CCCCCC.[C:24](=[O:26])=[O:25].O>O1CCCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]([CH3:2])[C:24]([OH:26])=[O:25])=[CH:5][CH:6]=1
Reactant: COc1ccc(C=C(Br)Br)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
1-(2,2-dibromovinyl)-4-methoxybenzene (17.38 g, 59.5 mmol) prepared in Reference Synthetic Example 1 was dissolved in tetrahydrofuran (230 ml) in nitrogen atmosphere, and a 2.59 mol/l n-butyllithium/hexane solution was dropwise added at −78° C. After the dropwise addition, the solution was returned to 0° C. and stirred for 90 minutes, and then cooled to −78° C. again, and crushed dry ice was added. After stirring for 30 minutes, water was added to the solution and the solution was concentrated under reduced pressure. The residue was diluted with diethyl ether, and extracted with a 1 mol/l sodium hydroxide aqueous solution twice. The obtained aqueous layer was acidified (pH=1) with hydrochloric acid and extracted with ethyl acetate twice. The obtained organic layer was washed with water and a saturated salt solution, dried over anhydrous sodium sulfate, subjected to filtration and concentrated under reduced pressure to give the desired compound (4-methxoyphenyl)propionic acid (9.73 g, 93%) as crude crystals.
Reaction SMILES: [CH2:1]([N:4]([C@H:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@H:17]([NH:26]C(=O)C(F)(F)F)[CH2:16]1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([N:4]([C@H:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[C@H:17]([NH2:26])[CH2:16]1)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCc1ccccc1)[C@@H]1C[C@@H](NC(=O)C(F)(F)F)c2cc(OC)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCN(C(=O)OCc1ccccc1)[C@@H]1C[C@@H](N)c2cc(OC)ccc21
Yield: 1 %

Procedure:
Step AP (3): benzyl trans-allyl(5-methoxy-3-(2,2,2-trifluoroacetamido)-2,3-dihydro-1H-inden-1-yl)carbamate (735 mg, 164 mmol) from Step AP (2) and K2CO3 (1.13 g, 8.20 mmol) were refluxed in 30 mL methanol and 3 mL H2O for 24 h. the reaction was concentrated to an oil, which was dissolved in 50 mL EtOAc and extracted three times with 50 mL brine. The organic layer was dried over Na2SO4, concentrated by rotary evaporation, and dried to give the title compound (600 mg, 100%). LC-MS (M+H)+=353.2; 1H NMR (400 MHz, CDCl3) δ ppm 1.63-1.83 (m, 1H) 2.80 (s, 1H) 3.51-3.65 (m, 1H) 3.81 (s, 3H) 3.88-4.03 (m, 1H) 4.24 (s, 1H) 4.99-5.19 (m, 4H) 5.23-5.54 (m, 1H) 5.81 (s, 1H) 6.80 (dd, J=8.31, 2.01 Hz, 1H) 6.83-6.97 (m, 1H) 7.01 (d, J=8.06 Hz, 1H) 7.18 (s, 1H) 7.26-7.41 (m, 4H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CO>CO.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][C:12](=[O:13])[CH2:17][CH2:18]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1CCC(c2ccc(F)cc2)CC1
Yield: 87 %

Procedure:
Hydrochloric acid (0.75 ml) was added to a solution 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decane (10 mmole) in methanol-water (2-1,100 ml). After stirring for 2 hr the methanol was removed in vacuo and the residue extracted with methylene chloride. Removal of the methylene chloride in vacuo gave the product as an oil (87%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH2:25]([O:32][CH2:33][C:34](O)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([O:32][CH2:33][C:34]([NH:18][C:15]1[CH:16]=[N:17][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([O:5][C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[C:2]([F:1])([F:23])[F:24])[CH2:11][CH2:10]2)=[CH:13][CH:14]=1)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Product: O=C(COCc1ccccc1)Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1

Procedure:
The title compound was prepared in the same manner as described for Example 25, step 2 from 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridin-3-amine and benzyloxyacetic acid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]1[C@@H:24]2[C@H:19]([CH2:20][CH2:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=32)[NH:18][CH2:17][CH2:16]1.[C:29]1([C:35]2[CH:48]=[CH:47][C:38]([C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH:45]=O)=[O:40])=[CH:37][CH:36]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.ClCCl>C(O)(=O)C.ClCCCl>[C:29]1([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][N:18]3[C@@H:19]4[C@H:24]([C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[CH2:21][CH2:20]4)[CH2:15][CH2:16][CH2:17]3)=[O:40])=[CH:47][CH:48]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=CCCCNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@@H]21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCCCCN1CCC[C@H]2c3ccccc3CC[C@@H]21)c1ccc(-c2ccccc2)cc1
Reaction time: 16 h
Yield: 45.6 %

Procedure:
Sodium triacetoxyborohydride (340 mg, 1.6 mmol) was added to a stirred mixture of trans-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (D8a, 200 mg, 1 mmol), 4-(4-phenylbenzoylamino)butyraldehyde (286 mg, 01.1 mmol) and acetic acid (1 drop) in 1,2-dichloroethane (10 ml) at room temperature. After stirring for 16 h, dichloromethane (20 ml) was added and the mixture was then washed with saturated aqueous K2CO3 (2×25 ml) and brine (25 ml). Drying (Na2SO4) and evaporation in vacuo afforded an oil which was purified by preparative TLC on Kieselgel using 10% methanol-ethyl acetate as eluent to give the title compound as a colourless solid (200 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:4][C:3]=1[CH3:19].[NH2:20][NH2:21]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:21][N:20]=2)=[CH:4][C:3]=1[CH3:19]
Reactant: NN
Reactant: Cc1cc(C(=O)CC(=O)c2ccccc2)ccc1F
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(-c3ccccc3)[nH]n2)ccc1F
Temperature: 75 °C
Reaction time: 3 h

Procedure:
1.7 g 1-(4-fluoro-3-methyl-phenyl)-3-phenyl-1,3-propanedione was dissolved in 20 mL of a solution of 1 N hydrazine in THF and stirred for 3 h at 75° C. The solvent was removed and the residue was crystallized to give 1.7 g of the desired compound.
Reaction SMILES: [C:1](=[NH:8])([S:6][CH3:7])[NH:2][C:3]([NH2:5])=[O:4].[CH3:9][N:10]=[C:11]=[O:12]>C(Cl)Cl>[C:3]([N:2]=[C:1]([S:6][CH3:7])[NH:8][C:11]([NH:10][CH3:9])=[O:12])(=[O:4])[NH2:5]
Reactant: CSC(=N)NC(N)=O
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)NC(=NC(N)=O)SC
Reaction time: 8 h

Procedure:
A mixture of 13 parts of methyl thioallophanimidate 74 parts of methylene chloride and 6 parts of methylisocyanate is refluxed for 2 hours. After standing overnight at room temperature, the solution is evaporated under vacuum to give crude methyl N-carbamoyl-4-methylthioallophanimidate (a compound of formula I).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:16]([CH3:18])=O)[O:7]2.[OH:20][C:21]1[CH:26]=[CH:25]C(S)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[C:6]([S:16][C:18]1[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=1)[O:7]2
Reactant: CC(C)Oc1cc(O)c2c(=O)cc(S(C)=O)oc2c1
Reactant: Oc1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(O)c2c(=O)cc(Sc3ccc(O)cc3)oc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A mixture of 7.01 g of 5-hydroxy-7-isopropoxy-2-methylsulfinylchromone (24.59 mmol), 3.72 g of 4-hydroxybenzenethiol (29.51 mmol), 4.07 g of potassium carbonate (29.51 mmol) and 170 ml acetone was stirred for 1 hour at room temperature. The reaction solution was neutralized with dilute hydrochloric acid and was then extracted twice with chloroform, and the organic layer was washed with saturated NaCl water and then dried over sodium sulfate anhydride. The solvent was distilled off under reduced pressure, and the crude product was subjected to recrystallization from ethanol-methanol, to give 6.64 g of 5-hydroxy-2-(4-hydroxyphenylthio)-7-isopropoxychromone (78% yield).
Reaction SMILES: ClC1C=C(C=CC=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[F:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][C:85]=1B(O)O>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:85]4[CH:86]=[CH:87][CH:88]=[CH:89][C:84]=4[F:83])=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: OB(O)c1ccccc1F
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccccc2F)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 25 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 2-fluorophenylboronic acid (37 mg, 0.2625 mmol) to produce the title compound (9 mg, 25% yield).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:9][CH:8]=1>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:1]=[N+:2]=[N-:3])=[CH:9][CH:8]=1
Reactant: COc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCCCN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
Sodium azide (3.07 g, 0.047 mol) was added to a solution of 1 (12.9 g, 0.04 mol) in anhydrous DMF (70 mL) and the reaction mixture was stirred 12 h at 80° C. (oil bath). Then solvent was removed at reduced pressure and the residual oil was treated with a mixture of CH2Cl2/ether 3:1 (100 mL). The resulting solution was washed with water (2×100 mL), brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and 7.6 g (95%) of 2 was obtained. The purity of 2 (99%) was determined by GC and TLC (eluent: hexane/ethyl acetate 1:1), Rf=0.84.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:20]3[C:21]4[C:16]([CH2:17][CH2:18][CH2:19]3)=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]=2[CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=3)[CH2:26][CH2:25]2)=[CH:6][CH:5]=1.Br[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[CH3:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([N:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][C:11]3[C:12]4=[C:21]5[C:16](=[CH:15][CH:14]=[CH:13]4)[CH2:17][CH2:18][CH2:19][N:20]5[C:10]=3[C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:5][CH:6]=3)[CH2:29][CH2:28]2)[CH:35]=1
Reactant: Cc1ccnc(N2CCN(CCc3c(-c4ccc(O)cc4)n4c5c(cccc35)CCC4)CC2)c1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1ccc(-c2c(CCN3CCN(c4cc(C)ccn4)CC3)c3cccc4c3n2CCC4)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 21.5 %

Procedure:
Under a nitrogen atmosphere, 0.25 g of sodium hydride was added to 50 ml of dry dimethylformamide, and the solution was heated to a temperature of 80° C. A solution of 4 g of 2-(4-hydroxyphenyl)-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (preparation see Example 8) in 75 ml of dimethylformamide was then added. The reaction mixture was stirred for 10 minutes, whereupon it assumed a greenish coloration. A solution of 1.6 g of ethyl 4-bromobutyrate in 40 ml of dimethylformamide was then added, and the reaction mixture was heated at 80° C. for 30 minutes. The reaction mixture was worked up by adding water and then extracting with dichloromethane. The organic phase was separated, washed, dried and concentrated. The residue which remained was purified by chromatography on a silica gel column, toluene to which amounts of ethanol increasing to 2% had been added being used as the eluent. 1 g of oily ethyl 4-[4-[1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-yl]-phenoxy]-butyrate was obtained.