Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:31][CH:30]=1)[C:9](=[O:28])[NH:10][C@H:11]([C:17](=[O:27])[NH:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=1[F:26])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])(C)(C)C.Cl.O1CCOCC1>C(#N)C>[F:26][C:20]1[CH:21]=[C:22]([I:25])[CH:23]=[CH:24][C:19]=1[NH:18][C:17](=[O:27])[C@@H:11]([NH:10][C:9](=[O:28])[C@H:8]([NH2:7])[C:29]1[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:33][CH:34]=1)[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C[C@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOC(C)(C)C)cc1)C(=O)Nc1ccc(I)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(C)(C)C[C@H](NC(=O)[C@H](N)c1ccc(OCCOC(C)(C)C)cc1)C(=O)Nc1ccc(I)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a solution of {(R)-[4-(2-tert-butoxy-ethoxy)-phenyl]-[(S)-1-(2-fluoro-4-iodo-phenylcarbamoyl)-3,3-dimethyl-butylcarbamoyl]-methyl}-carbamic acid tert-butyl ester (652 mg, 0.91 mmol) in acetonitrile (6 mL) was added 4 N hydrogen chloride in dioxane (1 mL, 4 mmol) and the mixture stirred at 40° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the residue suspended in ice cold water. The aqueous suspension was neutralized to basic pH with saturated aqueous sodium carbonate solution then extracted with dichloromethane (three times). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo and the residue purified by chromatography over silica gel gradient eluted from 100% dichloromethane up to 10% methanol/90% dichloromethane in 30 minutes. Concentration of the product containing fractions gave (S)-2-{(R)-2-amino-2-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetylamino}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide (490 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21])[CH2:14][CH3:15]>C(O)C>[Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH2:13][CH2:14][CH3:15])[CH:18]=1
Reactant: O=c1[nH]nc([N+](=O)[O-])c(Cl)c1Cl
Reactant: CCCOc1cc(CN)ccc1OC
Solvent: CCO
Product: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Reaction time: 15 h

Procedure:
A mixture comprising 8.0 g of 4,5-dichloro-6-nitro-3(2H)pyridazinone, 29.75 g of 3-n-propoxy-4-methoxybenzylamine and 160 ml of ethanol, was refluxed under stirring for 15 hours. Ethanol was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain an orange solid substance. This product was crystallized from a solvent mixture of methanol-water, to obtain 6.50 g of the above identified compound having a melting point of from 169° to 171° C. as orange crystals.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:22]([CH3:21])(=[O:24])=[O:23])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(C2CCCN2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a suspension of 2-(4-bromophenyl)pyrrolidine hydrogen chloride (250 mg, 0.952 mmol) in anhydrous methylene chloride (5 mL) was added triethylamine (0.66 mL, 4.76 mmol) under N2. The mixture was stirred at room temperature for 15 min. under N2. After 15 min., methanesulfonyl chloride (0.31 g, 2.72 mmol) was added and the mixture was stirred at room temperature under N2 overnight. Additional methanesulfonyl chloride (0.29 g, 2.54 mmol) and triethylamine (0.35 mL, 2.38 mmol) were added and stirred at room temperature for 4 h. The reaction was concentrated, and to the residue was added water (20 mL) and methylene chloride (18 mL), and the organic phase was washed with water (10 mL×3), brine (15 mL×1), dried over sodium sulfate and concentrated to afford the desired product (240 mg, 85.2% yield) which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.[NH2:14][C:15]1[N:20]=[CH:19][C:18]2[C:21]([CH3:29])([CH3:28])[C:22](=[O:27])[N:23]([CH:24]3[CH2:26][CH2:25]3)[C:17]=2[CH:16]=1>>[CH:24]1([N:23]2[C:17]3[CH:16]=[C:15]([NH:14][C:9]([C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:13])[F:12])=[N:4][CH:5]=4)=[O:11])[N:20]=[CH:19][C:18]=3[C:21]([CH3:28])([CH3:29])[C:22]2=[O:27])[CH2:26][CH2:25]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Reactant: O=C(O)c1cnc(C(F)(F)F)nc1
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3cnc(C(F)(F)F)nc3)ncc21

Procedure:
Prepared in analogy to example 26 from 2-(trifluoromethyl)pyrimidine-5-carboxylic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([NH2:19])=[CH:4][C:3]=1Br.[C:21]1([O-:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:17])[CH:12]=3)[C:7](=[O:18])[C:6]=2[C:5]([NH2:19])=[CH:4][C:3]=1[O:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [O-]c1ccccc1
Reactant: Nc1cc(Br)c(O)c2c1C(=O)c1ccc(Cl)cc1C2=O
Product: Nc1cc(Oc2ccccc2)c(O)c2c1C(=O)c1ccc(Cl)cc1C2=O

Procedure:
When 70.5 g of the 1-hydroxy-2-bromo-4-amino-7-chloroanthraquinone prepared above are subjected to a phenolate fusion as described in Example 467c, then 61 g, corresponding to 83% of theory, of 1-hydroxy-2-phenoxy-4-amino-7-chloro-anthraquinone are obtained, the colour shade of which on silica gel is a pink tinged with blue having the Indicator Number of 51 (Colour Index Hue Indication Chart).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:30].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:18])=[N:15][C:16]([Cl:30])=[C:10]2[CH:9]1[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: Cc1ccc(CCC2c3c(I)nc(C)n3CCN2C(=O)OC(C)(C)C)cc1C
Solvent: CO
Product: Cc1ccc(CCC2c3c(Cl)nc(C)n3CCN2C(=O)OC(C)(C)C)cc1C

Procedure:
According to the general procedure (GP12), chlorination of 8-[2-(3,4-dimethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.061 g; 2.142 mmol) and purification by FC (DCM/MeOH=40/1) gave the product 1-chloro-8-[2-(3,4-dimethyl-phenyl)-ethyl]-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as an orange oil (157 mg; 0.388 mmol). LC-MS: tR=1.01 min.; [M+H]+=404.50 g/mol.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([O:28][CH3:29])[C:16]=2[C:17](O)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:23]=[C:22]([C:24]([F:26])([F:27])[F:25])[CH:21]=[C:20]([O:28][CH3:29])[C:16]=2[C:17]([NH:11][C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:18])[CH2:14][CH2:13]1
Reactant: COc1cc(C(F)(F)F)cc(C2CC2)c1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: COc1cc(C(F)(F)F)cc(C2CC2)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light yellow solid, MS: m/e=397.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-cyclopropyl-6-methoxy-4-trifluoromethyl-benzoic acid (intermediate AS).
Reaction SMILES: Cl.[C:2]([O:6][C@H:7]([CH3:19])[C@@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:24]([O:23][C:21]([NH:9][C@H:8]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]#[N:18])=[O:11])[C@@H:7]([CH3:19])[O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](OC(C)(C)C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C#N
Yield: 100 %

Procedure:
A solution of (2S)-1-(O′-tert-butylthreoninyl)pyrrolidine-2-carbonitrile hydrochloride (35 mg, 0.12 mmol; prepared according to Jenkins et al., WO95/15309), benzyl chloroformate (32 mg, 0.13 mmol) and triethylamine (24 mg, 0.24 mmol) in dichloromethane (25 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant: chloroform:methanol; 98:2) yielding a white solid identified as the title compound (47 mg, 0.12 mmol, 100%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[ClH:9].NC(CS)C[N:13]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:23][C:18]=2[CH2:17][N:16]([C:30]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)=[O:31])[CH2:15][CH2:14]1>>[ClH:9].[C:32]1([C:30]([N:16]2[CH2:17][C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:21]=[CH:20][C:19]=3[N:13]([CH2:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:15]2)=[O:31])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: NC(CS)CN1CCN(C(=O)c2cccc3ccccc23)Cc2cc(-c3ccccc3)ccc21
Reactant: O=Cc1cccnc1
Agent: Cl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2cccnc2)c2ccc(-c3ccccc3)cc2C1

Procedure:
The title compound was prepared from nicotinaldehyde and the compound E of Example 2 by following the procedure described for the preparation of Example 6. MS (M+H): 470.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].CS([C:14]1[N:15]=[C:16]([CH2:40][CH2:41][CH3:42])[C:17]2[N:22]=[C:21]([C:23]3[CH:37]=[C:36]([CH3:38])[C:26]([O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:25]([CH3:39])[CH:24]=3)[O:20][C:18]=2[N:19]=1)(=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:38][C:36]1[CH:37]=[C:23]([C:21]2[O:20][C:18]3[N:19]=[C:14]([O:5][CH2:4][CH2:3][C:2]([F:7])([F:6])[F:1])[N:15]=[C:16]([CH2:40][CH2:41][CH3:42])[C:17]=3[N:22]=2)[CH:24]=[C:25]([CH3:39])[C:26]=1[O:27][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CCCc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Reactant: OCCC(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc(OCCC(F)(F)F)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.1 %

Procedure:
116 mg of 3,3,3-trifluoropropan-1-ol were added to 46 mg of sodium hydride (60% pure in mineral oil) in 1.5 ml of dry N,N-dimethylformamide. After 5 min, 111 mg of tert-butyl [4-(5-methanesulfonyl-7-propyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate were added, and the reaction was stirred initially at room temperature for 2 h and then at 80° C. for 15 min. For work-up, saturated aqueous citric acid solution was added, and the reaction was extracted three times with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative HPLC gave 12 mg (10%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[NH:2]=[C:1]([N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 12 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of N-methyl-piperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:9]([OH:39])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=[O:38])[NH:18][CH:19]([CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:32]1([CH2:31][CH2:30][CH2:29][CH:19]([NH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][CH:9]([OH:39])[CH:8]([NH2:7])[CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:12]2)=[O:38])[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CN1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccccc1)C(O)CN1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
(1-Benzyl-2-hydroxy-3-{3-[4-phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-piperidine-1-yl}-propyl)-carbamic acid tert-butyl ester (19) (194.4 mg; 0.3 mmol) is dissolved in methylene chloride (5 mL) at ambient temperature. Trifluoroacetic acid (5 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (10 mL) and water (100 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (50 mL) then extracted with methylene chloride (3×50 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (150 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](N(OC)C)=[O:13])[C:9]([N:18]2[CH2:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:13])[CH3:24])[C:9]([N:18]2[CH2:22][CH2:21][C@@H:20]([OH:23])[CH2:19]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1N1CC[C@@H](O)C1
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a mixture of 5-chloro-8-[(3R)-3-hydroxypyrrolidin-1-yl]-N-methoxy-N-methylquinoline-7-carboxamide (115 mg, 0.342 mmol) in tetrahydrofuran (0.5 mL) was added 1.40 M methylmagnesium bromide in tetrahydrofuran (1.5 mL, 2.0 mmol). The reaction was stirred at room temperature overnight, quenched with saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resultant residue was purified on silica gel, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product (95 mg, 95%). LCMS calculated for C15H16ClN2O2(M+H)+: m/z=291.1; found: 291.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([OH:20])(=O)[C:11]1[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:13]=[O:14]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:14])[O:20]2)=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=Cc1ccccc1C(=O)O
Product: O=C1OC(c2c[nH]c3ccccc23)(c2c[nH]c3ccccc23)c2ccccc21

Procedure:
This reaction sequence is further illustrated below under the preferred anhydrous conditions using as specific reactants, indole and phthalaldehydic acid to produce 3,3-di-(indol-3-yl) phthalide. ##STR6##
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:24])[C@@H:14]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:15])[NH:8]1)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[C:20]([O:19][C:17]([NH:16][C@@H:14]([CH3:15])[C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:7]([C:5]([OH:6])=[O:4])[NH:8]1)=[O:24])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)O)N1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A cooled (0° C.) solution of (S)-1-((S)-2-tert-butoxycarbonylamino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (3.007 g, 6.948 mmol) in tetrahydrofuran/water (60 mL, 5:1) was treated with lithium hydroxide monohydrate (874.4 mg, 20.844 mmol). After stirring at 0° C. for 40 minutes the reaction was quenched with hydrochloric acid (1 M, 50 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. Residual trichlorethanol was azeotroped off with toluene (3×) to provide (S)-1-((S)-2-tert-butoxycarbonylamino-propionyl)-hexahydro-pyridazine-3-carboxylic acid as a white solid which was then combined with (R)-1-(7-bromo-quinolin-2-yl)-ethylamine hydrochloride (1.998 g, 6.948 mmol) and suspended in anhydrous acetonitrile (60 mL) and tetrahydrofuran (10 mL). The suspension was cooled to 0° C. and subsequently treated with N,N-diisopropylethylamine (6 mL, 34.740 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (3.699 g, 9.727 mmol). After slowly warming to room temperature and stirring for 16 h, the reaction was quenched at 0° C. with hydrochloric acid (1 M, 70 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:4 to afford the title compound (3.702 g, 99%) as a white foam. 1H NMR (300 MHz, CDCl3) δ 1.38 (d, J=6.9 Hz, 3H), 1.43 (s, 9H), 1.47-1.55 (m, 2H), 1.58 (d, J=6.9 Hz, 3H), 1.60-1.78 (m, 2H), 2.22-2.31 (m, 1H), 2.65-2.78 (m, 1H), 3.39-3.52 (m, 1H), 4.55 (d, J=13.4 Hz, 1H), 5.18-5.34 (m, 2H), 5.36-5.45 (m, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.65 (dd, J=8.5, 1.6 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 8.04 (d, J=6.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.36 (s, 1H). LCMS (m/z) 536.1, 537.1 [M+H], Tr=2.58 min.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:9]=2)[N:4]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:3]=1.I[CH2:27][CH2:28][CH2:29][CH3:30].C([Li])(C)(C)C>>[CH2:27]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:9]=2)[N:4]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:3]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(Br)cn2[Si](C)(C)C(C)(C)C
Reactant: CCCCI
Agent: [Li]C(C)(C)C
Product: CCCCc1cn([Si](C)(C)C(C)(C)C)c2ccc(O[Si](C)(C)C(C)(C)C)cc12

Procedure:
In analogy to the procedure described in example 27 c], 3-bromo-1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole was reacted with 1-iodobutane in the presence of tert-butyllithium to form 3-butyl-1-(tert-butyl-dimethyl-silanyl)-5-(tert-butyl-dimethyl-silanyloxy)-1H-indole as dark brown oil.
Reaction SMILES: Cl.[C:2]1([C:8]2[NH:13][C:12]3[CH:14]=[N:15][CH:16]=[CH:17][C:11]=3[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([Cl:26])=[O:25])([O-:20])=[O:19]>>[ClH:26].[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:10]1[C:11]2[CH:17]=[CH:16][N:15]=[CH:14][C:12]=2[NH:13][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9]1)=[O:25])([O-:20])=[O:19]
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 78.6 %

Procedure:
3.8 g (0.015 moles) of 3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with m-nitrobenzoyl chloride as described in Example 3 to obtain 1-(m-nitrobenzoyl)-3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 78.6%; m.p.: 206°-207° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Reaction time: 0.92 h
Yield: 104.5 %

Procedure:
To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (11.98 g, 58.4 mmol, 1 equiv) in THF (80 mL) at 23° C. was added a saturated solution of sodium bicarbonate (200 mL) followed by benzyl chloroformate (9.19 mL, 64.2 mmol, 1.1 equiv). The reaction was stirred for 55 min then partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was separated, washed with saturated brine solution (200 mL), dried (MgSO4), filtered and concentrated to give 20.4 g of tan solid. This material was used in the next step without further purification.
Reaction SMILES: N1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:7])C=CN=C1.[CH3:13][O:14][CH:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C(O)=O>ClCCl>[N:8]1([C:6](=[O:7])[CH:15]([O:14][CH3:13])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(C(=O)O)c1ccccc1
Solvent: ClCCl
Product: COC(C(=O)n1ccnc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Di-(1H-imidazol-1-yl)methanone (1.073 g, 6.62 mmol) was added in small portions to a stirred solution of 2-methoxy-2-phenylacetic acid (1.047 g, 6.30 mmol) in dichloromethane (3 mL) at room temperature under argon. The reaction mixture was stirred at room temperature overnight. The mixture was washed twice with water, dried over MgSO4 and concentrated yielding 1-(1H-imidazol-1-yl)-2-methoxy-2-phenylethanone (1.118 g, 82%).