Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:22])=[CH:13][C:14]4[C:19]([CH:20]=3)=[CH:18][C:17]([Br:21])=[CH:16][CH:15]=4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCOc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2

Procedure:
17.85 g (0.05 mol) of 3-(1-adamantyl)-6-bromo-2-naphthol and 200 ml of DMF were introduced into a three-necked flask under a stream of nitrogen. 1.8 g (0.06 mol) of sodium hydride (80% in oil) was added portionwise and the reaction mixture was stirred until gas evolution had ceased. 6.9 ml (0.06 mol) of methoxyethoxymethyl chloride were then added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and heptane (40/60). 19.5 g (87%) of the expected compound were collected, which compound had a melting point of 99°-100° C.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH3:25])[C:17]([NH:16][C:11]2[C:12]([CH2:13][OH:14])=[C:7]([O:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:8]=[C:9]([CH3:26])[N:10]=2)=[C:22]([CH3:23])[CH:21]=1
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(Cl)cc2C)c1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(Cl)cc2C)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-6-methyl-2-(4-chloro-2,6-dimethyl-phenylamino)nicotinic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux overnight. The mixture was quenched with dilute HCl and stirred for 30 minutes, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a brown oil. After silica gel column chromatography, the title compound was obtained as a green oil. 1H NMR(CDCl3) d 7.02(s,2H), 6.83(brs,1H), 4.78(s,2H), 4.14(m,1H), 2.2(s,3H), 2.13(s,6H), 1.66(m,4H), 0.93(9t,6H) ppm.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21]OS(C)(=O)=O)[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[K+].[N-:29]=[N+]=[N-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[ClH:44]>CN(C=O)C.CO.CCOCC.O>[ClH:44].[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]([CH2:20][CH2:21][NH2:29])[CH2:15][CH2:14][CH2:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: NCCC1CCCc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 48 h
Yield: 17 %

Procedure:
A solution of methanesulfonic acid 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethyl ester (1.12 g, 2.84 mmol) in thy DMF (25 mL) was stirred under argon at room temperature. Solid potassium iodide (0.25 g) and sodium azide (0.185 g, 2.84 mmol) were added, and the reaction mixture was allowed to stir for 48 hours. The reaction mixture was poured into 500 mL of water, and the aqueous mixture was extracted four times with 150 mL of EtOAc. The combined organic layers were washed with water, brine, dried (MgSO4), and evaporated under reduced pressure to give an oil that was purified by eluting through silica gel with hexanes:EtOAc (3:2). After solvent removal, the resulting oil was dissolved in dry THF, cooled to 0° C., and 5.68 mL of lithium aluminum hydride in THF (5.68 mmol) was added dropwise via syringe to the stirring reaction mixture. The reaction mixture was allowed to warm to room temperature (about 30 minutes) and was quenched by addition to 250 mL of water. The aqueous solution was extracted twice with 250 mL of EtOAc, and the combined organic layers were washed with water, brine, dried (MgSO4), and evaporated under reduced pressure to give an oil. The oil was dissolved in MeOH, 2 mL of 2M HCl in Et2O) was added, and the solution was gently warmed, then cooled. The resulting residue was recrystallized from MeOH/Et2O to afford 0.17 g (0.483 mmol, 17%) of 2-(6-benzenesulfonyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-ethylamine hydrochloride salt. MS: 316 (M+H)+.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:36]>CO.C1COCC1>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([O:20][CH3:36])=[O:19])[CH:15]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Reaction time: 6 h

Procedure:
To a solution of 0.037 g (0.08 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-carboxypyrrolidine in 0.6 mL of MeOH and 1.2 mL of THF at rt was added 0.2 mL (0.4 mmol) of TMSCHN2 (2M in hexanes) and the reaction mixture was stirred for 6 h. The reaction mixture was concentrated and the residue was purified by chromatography (silica, acetone: hexanes, 1:3) to give the title compound.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]1=[O:3].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:12][C:4]1[C:2](=[O:3])[O:1][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=c1ccc2ccccc2o1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Nc1cc2ccccc2oc1=O

Procedure:
A 2-neck-flask provided with a drying tube and a dropping means in a water bath of a temperature of from 20° to 25° C. is charged with 1 mmol coumarin, and 60 ml of dioxane are added while stirring (with a magnetic stirrer) to dissolve the coumarin. Then 1,1 mmol pyridine are added while stirring, whereby a precipitate of a pyridine-aminocoumarin-complex is formed. Then 1,1 mmol phenylacetyl chloride, dissolved in 2 ml dioxane, are added dropwise within 2 minutes. The reaction mixture is stirred for 3 hours and then poured on an equal amount of ice, the mixture is acidified with 32% HCl until no more precipitate is formed. After the dissolution of the ice further HCl is added until no more precipitate is formed, then it is filtered using a sucking filter and washed with ice-cooled water until the filtrate is neutral. The obtained amide is twice recrystallized from ethanol (about 150 ml for PMC and about 30 ml for PFC) and dried sharply. The obtained coumarinyl derivatives have to be stored in a refrigerator under anhydrous and light-schielded conditions. The yields were 67 to 77% for PMC and 52 to 57% for PFC.
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:28])[NH:11][CH:12]2[CH2:15][N:14]([CH:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:13]2)=[O:7])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[NH2:35][CH2:36][CH2:37][OH:38]>>[OH:38][CH2:37][CH2:36][NH:35][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:28])[NH:11][CH:12]2[CH2:13][N:14]([CH:16]3[CH2:21][CH2:20][CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:15]2)=[O:7])=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32]
Reactant: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: NCCO
Product: O=C(CNC(=O)c1ccc(NCCO)c(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid from the coupling of 4-fluoro-N-{[1-(4-phenyl-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide (as prepared in Example 71) and 2-amino-ethanol (Aldrich) using the procedure described in Example 65.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([CH:14]=[C:15](OCC)[NH:16][CH3:17])#[N:13]>N1C=CC=CC=1>[C:12]([CH:14]=[C:15]([NH:16][CH3:17])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: CCOC(=CC#N)NC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: c1ccncc1
Product: CNC(=CC#N)NCCSCc1[nH]cnc1C
Reaction time: 5 h

Procedure:
4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole (3.5 g) was added to a solution of 1-cyano-2-ethoxy-2-methylaminoethylene in pyridine (3.1 g) and the solution was stirred for 5 hours at 100°. The product was chromatographed on a column of neutral alumina with elution by chloroform/ethyl acetate (1:1) to give the title compound as a glass.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH2:22])=[C:20]([O:27][CH3:28])[CH:19]=1>>[Cl:17][C:18]1[C:24]([O:25][CH3:26])=[CH:23][C:21]([NH:22][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)[C:5]([F:16])=[CH:4][N:3]=2)=[C:20]([O:27][CH3:28])[CH:19]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: COc1cc(Cl)c(OC)cc1N
Product: COc1cc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c(OC)cc1Cl

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 4-chloro-2,5-dimethoxyaniline gave N2-(4-chloro-2,5-dimethoxyphenyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.04 (d, 1H, J=5.4 Hz), 7.46 (s, 1H), 7.17 (m, 2H), 7.03 (m, 2H), 6.72 (dd, 1H, J=1.8 and 7.8 Hz), 3.85 (s, 3H), 3.52 (s, 3H); LCMS: purity: 98%; MS (m/e): 390 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5](=[O:25])[CH2:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH:9]=1)C.[OH-].[Na+]>CO>[O:25]=[C:5]([CH2:6][C:7](=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[CH:9]=1)[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc(C2CCCc3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)CC(=O)c1cccc(C2CCCc3ccccc32)c1

Procedure:
Isomer B: In a similar manner to the above, 2,4-dioxo-4-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]butyric acid ethyl ester (isomer B from above) was reacted in 2 mL methanol with 1 mL 1M sodium hydroxide to afford the title compound as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[N:22]([C:24]([CH:28]=[CH2:29])=[C:25]([CH3:27])[N:26]=4)[N:23]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[CH3:27][C:25]1[N:26]=[C:21]2[CH:20]=[C:19]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH2:7])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)=[N:23][N:22]2[C:24]=1[CH:28]=[CH2:29]
Reactant: C=Cc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nn12
Agent: Cl
Solvent: C1COCCO1
Product: C=Cc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12
Yield: 18.3 %

Procedure:
244 mg Of the crude {1-[4-(2-methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl]-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester were stirred in 16.1 mL 4M hydrogen chloride in dioxane for 22 hours at room temperature. The reaction mixture was worked up as described in the previous example. The crude product (178 mg) was purified by HPLC to yield 35.3 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][S:11][CH2:10][CH2:9]2)[N:5]=[CH:4][C:3]=1[NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+].[C:27]1([CH3:36])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>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.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([NH:14][C:3]1[CH:4]=[N:5][C:6]([N:8]2[CH2:13][CH2:12][S:11][CH2:10][CH2:9]2)=[CH:7][C:2]=1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH3:36])=[O:20]
Reactant: CC(C)(C)C(=O)Nc1cnc(N2CCSCC2)cc1I
Reactant: Cc1ccccc1B(O)O
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(N2CCSCC2)ncc1NC(=O)C(C)(C)C
Temperature: 80 °C

Procedure:
A mixture of 4.05 g (10.0 mmol) N-(4-iodo-6-thiomorpholin-4-yl-pyridin-3-yl)-2,2-dimethyl-propionamide, 54 ml toluene, 16 ml 2 N sodium carbonate solution, 347 mg (0.3 mmol) tetrakis(triphenylphosphine)palladium(0), 67 mg (0.3 mmol) palladium(II) acetate and 1.50 g (11.0 mmol) o-tolylboronic acid was heated under argon at 80° C. for 18 h. After cooling to room temperature, the aqueous phase was separated and washed twice with ethyl acetate. The combined organic layers were washed with 50 ml brine, dried (sodium sulfate) and evaporated. Purification by flash-chromatography gave 3.57 g (quantitative) of the title compound as a light brown solid.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:25]([N:27]([CH:41]([CH3:43])[CH3:42])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)=[O:26])[C:22]([CH3:24])=[CH:23][C:18]=2[O:17][C:16]([CH3:45])([CH3:44])[C:15]1=[O:46])=O)C1C=CC=CC=1>[C].[Pd].CO>[NH2:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:25]([N:27]([CH:41]([CH3:42])[CH3:43])[C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])[CH2:29]3)=[O:26])[C:22]([CH3:24])=[CH:23][C:18]=2[O:17][C:16]([CH3:44])([CH3:45])[C:15]1=[O:46]
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCNC(=O)OCc1ccccc1)C(=O)C(C)(C)O2
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl (3R)-3-[{[4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (1.14 g) were added a 10% palladium carbon (500 mg) and methanol (30 ml), and the mixture was stirred at room temperature under hydrogen atmosphere for 2 hours. After the reaction was complete, the mixture was filtered and concentrated. The obtained residue (900 mg) was used in the subsequent reaction without further treatment.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12](N(C)OC)=[O:13].CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH:12]=[O:13]
Reactant: CON(C)C(=O)C1OCCc2c(Br)cccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: O=CC1OCCc2c(Br)cccc21
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-N-methyl-N-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide (3.0 g, 10 mmol) in 60 mL of anhydrous THF was cooled to −30° C. and then DIBAL-H (20 mmol) was added. The mixture was stirred at −30° C. for 1 hours. The reaction was quenched with water, extract with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude 5-bromo-3,4-dihydro-1H-isochromene-1-carbaldehyde was used for next step without purification.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:27](=[O:28])[C:19]3([CH2:21][CH:20]3[C:22]([O:24]CC)=[O:23])[C:14]3=[N:15][N:16]=[C:17]([CH3:18])[N:13]3[C:12]3[CH:29]=[CH:30][CH:31]=[CH:32][C:11]2=3)=[CH:6][CH:5]=1.Cl>CO.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:27](=[O:28])[C:19]3([CH2:21][CH:20]3[C:22]([OH:24])=[O:23])[C:14]3=[N:15][N:16]=[C:17]([CH3:18])[N:13]3[C:12]3[CH:29]=[CH:30][CH:31]=[CH:32][C:11]2=3)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CC12C(=O)N(c1ccc(Cl)cc1)c1ccccc1-n1c(C)nnc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C21CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaOH (48 mg, 1.2 mmol) was added to a solution of ethyl 6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane]-2′-carboxylate (100 mg, 0.24 mmol) in MeOH (10 mL) and water (4 mL). It was stirred at room temperature overnight. The solution was adjust to pH=5 using HCl solution (1 M), then concentrated, adding dichloromethane (5 mL), filtered and the filtrate was concentrated to give crude 6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane]-2′-carboxylic acid, which was used in the next step directly. LRMS (M+H)+: 394 m/z.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[C:8]([C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[CH:15]=O)([CH3:11])([CH3:10])[CH3:9].N1CCCCC1>C(O)C>[C:21]([C:18]1[CH:17]=[C:14]([CH:15]=[C:7]2[S:1][C:2](=[S:3])[NH:4][C:5]2=[O:6])[CH:13]=[C:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:19]=1[OH:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C1CSC(=S)N1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Yield: 69.5 %

Procedure:
To a solution of 14.6 g (110 mmol) of rhodanine and 25.7 g (110 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde in 150 ml of ethanol, 1.08 ml (11.0 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 26.71 g of the desired compound (69.7% yield, pale yellow crystals).
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([F:21])[CH:10]=1)[C:3](=[O:8])[C:4]([O:6]C)=[O:5].[OH-].[K+]>CO>[CH3:1][CH:2]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([F:21])[CH:10]=1)[C:3](=[O:8])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)C(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a solution of 2.4 g of methyl 3-methyl-3-(2-fluoro-4-biphenylyl)-pyruvate in 40 ml of methanol was added a solution of 2.0 g of potassium hydroxide in 20 ml of methanol, and the resulting mixture was stirred at room temperature for 30 minutes. Subsequently, the methanol was removed from the mixture by distillation under reduced pressure. The residue was charged with water, and insoluble matter was removed therefrom by extraction with ethyl acetate. The extraction mother liquor was acidified with hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was successively washed with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed by distillation under reduced pressure to obtain 1.8 g of 3-methyl-3-(2-fluoro-4-biphenylyl)-pyruvic acid. The yield was 79%.
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([NH2:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:21]([CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[CH2:32][CH2:31]2)[CH2:20]1>CN(C)C=O>[NH:41]1[C:42]2[C:38](=[CH:37][C:36]([N:33]3[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C@H:21]4[C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[N:19]([C:1](=[O:5])[C:2]([NH2:4])=[O:3])[CH2:20]4)[CH2:35][CH2:34]3)=[CH:44][CH:43]=2)[CH:39]=[CH:40]1
Reactant: NC(=O)C(=O)O
Reactant: c1ccc2c(c1)NC[C@H]2CCN1CCN(c2ccc3[nH]ccc3c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)C(=O)N1C[C@@H](CCN2CCN(c3ccc4[nH]ccc4c3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of oxalamic acid (2.35 g, 0.026 mol) and 1,1′-carbonyldiimidazole (4.66 g, 0.029 mol) in dry N,N-dimethyl formamide (50 mL) was slowly added a solution of 5-{4-[(S)-2-(2,3-dihydro-1H-indol-3-yl)-ethyl]-piperazin-1-yl}-1H-indole (8.3 g, 0.024 mol) in N,N-dimethyl formamide (75 mL). The resulting mixture was stirred at room temperature for 1 h, filtered and poured onto brine. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/heptane/triethylamine 70:25:5) to give the title compound as an oil (6.5 g). The oil was precipitated from ethyl acetate to give a powder (4.1 g). Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)=[C:24]([F:38])[CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30](=[CH:16][C:13]2[NH:12][C:9]4[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=4[C:14]=2[CH3:15])[C:31](=[O:37])[NH:32]3)=[C:24]([F:38])[CH:23]=1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2F)N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(-c5ccc(Cl)cc5F)c43)c(C)c2C1=O
Yield: 38.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(4-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(4-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (35 mg, 38.9%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(#N)C>[Br:16][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([NH2:8])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)ccn1
Solvent: CC#N
Product: Nc1cc(Cl)c(Br)cn1
Reaction time: 14 h
Yield: 100.7 %

Procedure:
To a stirred solution of 4-chloropyridin-2-amine (8 g, 62.2 mmol) in acetonitrile (600 mL) at rt was added NBS (11.08 g, 62.2 mmol) in portions and the reaction was stirred for 14 h. The reaction mixture was concentrated under reduced pressure. The residue was reconstituted in ethyl acetate and water. The organics were extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), and dried over sodium sulphate. The organics were concentrated under reduced pressure to afford 5-bromo-4-chloropyridin-2-amine as yellow solid (13 g, 99% yield) that was used without further purification in the next step. LCMS (ESI) m/e 207.0 [(M+H)+, calcd for C5H5BrClN2 206.9]; LC/MS retention time (method B): tR=0.8 min; 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 6.63 (s, 1H), 4.59 (s, 2H).