Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].[H-].[Na+].Br[CH:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=[CH:12]2)#[N:2]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC(C(=O)OCC)n1ccc2cc(-c3ccccc3C#N)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
5-(2-Cyanophenyl)indole (5.04 moles, 1.1 g) in 70 ml THF was treated with sodium hydride (255 mg, 50% in mineral oil) and stirred at 0° C. for 30 minutes. Ethyl 2-bromooctanoate (5.5 mmoles) in 40 ml THF was added dropwise. The reaction was stirred at room temperature for 4 hours, cooled, poured onto ice, extracted with ethyl acetate. The organic phase was dried and concentrated. The intermediate was chromatographed over silica gel eluted with 20% ether in hexane. The reaction yielded 1.1 g of ethyl 2-[5-(2-cyanophenyl)indol-1-yl]octanoate. (MS)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])/[CH:5]=[CH:6]/[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[NH:20]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:6]/[C:7]([N:20]2[CH2:26][CH2:25][C:24](=[O:27])[NH:23][CH2:22][CH2:21]2)=[O:9])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: O=C1CCNCCN1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
A solution of 9.77 g (43.65 mmol) of (E)-3,4-dichlorocinnamic acid in 250 ml of Dichloromethane was treated at RT with 3 drops of DMF. 4.15 ml (48.02 mmol, 1.1 eq) of oxalyl chloride in 30 ml dichloromethane were added dropwise and stirring was continued for 3 h. The solution was evaporated, redissolved in 170 ml of dichloromethane, cooled (0° C.) and treated with a solution of 4.48 g (39.29 mmol, 0.9 eq) of 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one and 12.17 ml (87.30 mmol, 2 eq) of triethylamine in 80 ml of dichloromethane. The reaction was warmed up over night to RT, and then partitioned between dichloromethane/MeOH 9:1 (×3)/aqueous 10% KHSO4, the organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried over Na2SO4 and evaporated. The residue was dissolved and evaporated with toluene and crystallized with dichloromethane/Et2O to give 7.99 g (58%) of the titled compound as white solid. MS: 312.8 (MH+, 2Cl).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[CH:17][C:18]([O-:20])=[O:19])=[CH:3][CH:2]=1.[CH2:27]([N:34]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][CH3:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[C:49]1(C)C=CC=CC=1>>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:16]([CH2:17][C:18]([O:20][CH3:49])=[O:19])[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[C:8]2[N:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][N:34]([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:41])=[CH:3][CH:2]=1
Reactant: CNCCCCCN(Cc1ccccc1)Cc1ccccc1
Reactant: Cc1ccccc1
Reactant: O=C([O-])C=Cc1ccccc1N=C=Nc1ccc(-c2ccccc2)cc1
Product: COC(=O)CC1c2ccccc2N=C(N(C)CCCCCN(Cc2ccccc2)Cc2ccccc2)N1c1ccc(-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
To a solution of methyl 3-[2-(4-biphenylyliminomethyleneamino)phenyl]acrylate (11) (1.12 g, 3.15 mmol) in toluene (100 ml) was added N,N-dibenzyl-N′-methylpentane-1,5-diamine (18) (1.87 g, 6.30 mmol). Then, the reaction mixture was stirred for 2 hours and extracted with dichloromethane three times. The combined organic phase was dried with anhydrous magnesium sulfate and distilled under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent: ethyl acetate:hexane:dichloromethane=1:2:1) to give the target compound as a yellow liquid (2.56 g, quantitative yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:11])=[N:5][C:6]([Cl:10])=[C:7]([F:9])[CH:8]=1.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:23])[CH3:22])=[CH2:13].[H-].[Na+].O>CN(C=O)C>[Cl:11][C:4]1[C:3]([CH2:2][N:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:12]=[CH2:13])[C:21](=[O:23])[CH3:22])=[CH:8][C:7]([F:9])=[C:6]([Cl:10])[N:5]=1
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Reactant: C=Cc1ccccc1NC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccccc1N(Cc1cc(F)c(Cl)nc1Cl)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a stirred mixture of 1B (0.5 g, 1.93 mmol) and N-(2-vinyl-phenyl)-acetamide bb (0.314 g, 1.95 mmol) in DMF (5 mL) was added NaH (47 mg, 1.95 mmol) at 0° C. The reaction mixture was stirred for 30 minutes at room temperature, then poured into H2O (50 mL) and extracted with Et2O (20 mL). The Et2O layer was washed with H2O (2×20 mL), dried (MgSO4), filtered and concentrated in vacuo to give 1C (0.63 g, 96%). HPLC Rt=3.212 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].[C:6]1(=[O:13])C[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(OCC)=O>CCOCC.O>[CH:3]([CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:13])=[O:5]
Reactant: CCO
Reactant: O=C1CCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: O
Solvent: CCOCC
Product: O=CC1CCCCCC1=O
Reaction time: 20 h
Yield: 99 %

Procedure:
In an argon atmosphere, sodium hydride (60%; 55.2 g, 1.38 mol) was suspended in ether (2 L), and ethanol (2.5 mL) was added thereto at room temperature. Then, a liquid mixture of cycloheptanone (141 g, 1.26 mol) and ethyl formate (152 mL, 1.84 mol) was added dropwise to the mixture over 2 hours, and the resulting mixture was stirred at the same temperature for 20 hours. Ethanol (25 mL) was added to the reaction solution, subsequently water (1.2 L) was added, and the mixture was separated. The resultant was extracted with a 10% (w/v) aqueous solution of sodium hydroxide, and then the aqueous layers were combined and washed with ether. 15% (v/v) hydrochloric acid was added to the aqueous layer under ice cooling to adjust the aqueous layer to pH 3 to 4, and then the mixture was extracted twice with ether, washed with saturated solution of sodium chloride, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and thus the title compound (174 g, 99%) was obtained as a pale orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:19][N:20](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:21].F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CNC>C1COCC1>[CH3:19][N:20]([CH3:21])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:8][C:9]=2[CH:15]=1)=[O:18]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)Cc1nc2ccc(C(=O)O)cc2[nH]1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nc2ccc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(Ethoxycarbonyl)methyl]benzimidazole-5-carboxylic acid (1.0 eq) was dissolved in THF. HBTU (1.1 eq) and diisopropylethylamine (2.0 eq) were added, followed by dimethylamine (2.0 M in THF, 1.1 eq). The reaction was stirred at room temperature overnight then concentrated and the resulting residue was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to afford the desired compound. LC/MS m/z 276.2 (MH+), Rt 1.18 minutes.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].ClC(Cl)(Cl)C([C:9]1[NH:10][CH:11]=[CH:12][CH:13]=1)=O.[CH3:16][OH:17]>>[NH:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[C:1]([O:17][CH3:16])=[O:2]
Reactant: C[O-]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: CO
Agent: [Na+]
Agent: [Na]
Product: COC(=O)c1ccc[nH]1
Reaction time: 2.5 h

Procedure:
A solution of sodium methoxide, prepared by dissolving sodium (34.0 g) in 4.0 L of methanol, is added to a solution of 2480 g of 2-(trichloroacetyl)-pyrrole in 6.0 L of methanol over a period of 1.5 hours under an atmosphere of nitrogen. There is an exotherm to 35° during the addition. Stirring is continued at room temperature for 2.5 hours, then the solution is concentrated to dryness in vacuo. The residue is dissolved in 9.0 L of ether and the solution is washed with 2×700 mL of water, dried over anhydrous magnesium sulfate (250 g), and stirred for 1 hour with charcoal (20 g). The mixture is filtered and the filtrate is concentrated to dryness to vacuo to give methyl pyrrole-2-carboxylate, m.p. 73°-74'.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH:10]1([CH2:16][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=Cc1ccc(OCC2CCCCC2)cc1

Procedure:
4-Hydroxybenzaldehyde (244 g) and 354 g of cyclohexylmethylbromide were added to 1 liter of methanol containing 414 g of anhydrous potassium carbonate (3.0M). The mixture was heated to reflux temperature overnight after which it was poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated in vacuo to yield the desired subtitled intermediate.
Reaction SMILES: CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+].[CH2:16]([N:23]([S:31]([CH2:34][CH2:35][CH2:36]Cl)(=[O:33])=[O:32])C(=O)OC(C)(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:38]1([C:44]2[C:45]3[CH:46]=[CH:47][C:48]([C:68]([O:70][CH3:71])=[O:69])=[CH:49][C:50]=3[N:51]3[C:58]=2[C:57]2[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=2[O:55][CH2:54][C@@H:53]([O:63][CH2:64][CH2:65][NH:66][CH3:67])[CH2:52]3)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC#N>[CH2:16]([NH:23][S:31]([CH2:34][CH2:35][CH2:36][N:66]([CH3:67])[CH2:65][CH2:64][O:63][C@H:53]1[CH2:52][N:51]2[C:50]3[CH:49]=[C:48]([C:68]([O:70][CH3:71])=[O:69])[CH:47]=[CH:46][C:45]=3[C:44]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[C:58]2[C:57]2[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=2[O:55][CH2:54]1)(=[O:32])=[O:33])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)S(=O)(=O)CCCCl
Reactant: CNCCO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OCCN(C)CCCS(=O)(=O)NCc1ccccc1)COc1ccccc1-3
Temperature: 200 °C
Yield: 23 %

Procedure:
DIPEA (2 eq.), K2CO3(4 eq.) and tert-butyl benzyl[(3-chloropropyl)sulfonyl]carbamate (was added to a solution of methyl (7S)-14-cyclohexyl-7-[2-(methylamino)ethoxy]-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.08 M) in MeCN. The mixture was heated in the microwave at 200° C. for 30 min. The resulting mixture was filtered, concentrated in vacuo, and the residue purified by RP-HPLC (WATERS XTERRA column, C18, 5 um, 19×150 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound (23%) as a white powder. (ES+) m/z 674 (M+H)+.
Reaction SMILES: [P:1]([O:6][CH3:7])([O:4][CH3:5])[O:2]C.[Cl:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:19])([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=1.CCl>>[Cl:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]([CH3:18])([CH3:19])[C:15]([P:1](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:16])=[CH:11][CH:10]=1
Reactant: COP(OC)OC
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)Cl
Agent: CCl
Product: COP(=O)(OC)C(=O)C(C)(C)Oc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
An amount of 10.6 g (86 mmol) of trimethyl phosphite was added dropwise to 20.0 g (86 mmol) of p-chlorophenoxyisobutyryl chloride cooled to 0° C. As verification of the reaction, evolution of methyl chloride could be observed. Distillation under reduced pressure gave 19.0 g (62 mmol) of dimethyl p-chlorophenoxyisobutyrylphosphonate as an almost colorless oil.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](O)(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10](=[O:14])[CH:11]=[CH:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OCCCCCCCC
Temperature: 125 °C
Yield: 81.1 %

Procedure:
Octan-1-ol (221 g), crotonic acid (194 g), PTSA (6.4 g), and toluene (300 mL) were charged into a 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a Dean-Stark trap, and a condenser. The reaction mixture was heated to reflux at about 120-130° C. Water was removed azeotropically. The reaction was aged at reflux for about 7-8 hours until no more water evolved. The reaction mixture was cooled to room temperature and quenched with water (400 mL). The organic layer was separated and subsequently washed with sodium carbonate (5%, 300 mL), and further fractional distilled to provide but-2-enoic acid octyl ester (273 g) with a boiling point of 123° C. at 11 mmHg.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.OO.[OH2:15].C(O)(=[O:18])C>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:8][S:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=1)(=[O:18])=[O:15]
Reactant: CC(=O)O
Reactant: CSc1cc(C(F)(F)F)nn1C
Reactant: O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cn1nc(C(F)(F)F)cc1S(C)(=O)=O

Procedure:
0.25 g of Compounds (14) was dissolved in 20 ml of acetic acid. While stirring, 0.44 g of 30% hydrogen peroxide solution, and 0.04 g of sodium tungstate dihydrate were added sequentially. The mixture was stirred at room temperature for 12 hours, then poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to produce 0.29 g of 5-methanesulfonyl-1-methyl-3-(trifluoromethyl)pyrazole (2-1).
Reaction SMILES: [C:1]1([C:7]([NH:15][C:16](=O)[CH:17]([O:20][CH3:21])[CH2:18][CH3:19])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.O=C(Cl)OC(Cl)(Cl)[Cl:34]>C(Cl)Cl>[C:1]1([C:7]([N:15]=[C:16]([Cl:34])[CH:17]([O:20][CH3:21])[CH2:18][CH3:19])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCC(OC)C(=O)NC(=Cc1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OC)C(Cl)=NC(=Cc1ccccc1)c1ccccc1
Yield: 153.9 %

Procedure:
A solution of 21 g of the product of Step B, 300 ml of methylene chloride and 49.5 ml of triethylamine was cooled to -40° C. and at -40° C. a solution of 9.42 g of diphosgene in 90 ml of methylene chloride was added. The residue, after returning the temperature to 20° C. and concentrating the mixture under reduced pressure, was taken up in ether and filtered. The filtrate was concentrated under reduced pressure to obtain 23 g of the expected product.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(Cl)Cl.[CH2:15]([N:17]([CH2:37][CH3:38])[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH:32]=2)=[CH:24][CH:23]=1)[CH3:16]>O>[C:1]([C:32]1[C:31]2[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=2[O:29][C:28]=1[C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:15][CH3:16])[CH2:37][CH3:38])=[CH:23][CH:24]=1)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCOc1ccc(-c2cc3ccccc3o2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(OC)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 1.02 g. (0.006 mol.) of p-anisoyl chloride in 75 ml. of methylene chloride was added 2.0 g. (6.2 mmol.) of the hydrochloride salt of 2-[4'-(3-diethylaminopropoxy)phenyl]benzofuran. The reaction mixture was cooled to 0°, 3.3 ml. (0.024 mol.) of stannic chloride was added and the resulting mixture was stirred for 10 minutes at 0° then for 2.75 hours at 25°. The mixture was then poured into water and stirred vigorously. The layers were separated and the organic phase was washed with 10% aqueous sodium carbonate solution and water, dried (MgSO4) and concentrated to give the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14].C(N(CC)CC)C.[S:22]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23]1>C(#N)C>[S:22]1[CH:26]=[CH:25][C:24]([S:27]([O:1][C:2]2[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:14])(=[O:29])=[O:28])=[CH:23]1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: COc1cc(I)c2c(c1O)CNC2=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(I)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Yield: 80.6 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-5-methoxy-7-iodoisoindolinone (0.265 g, 0.869 mmol) was dissolved in acetonitrile (8.0 mL), and the solution was treated with triethylamine (0.242 mL, 1.74 mmol) and 3-thiophenesulfonyl chloride (0.191 g, 1.04 mmol) to obtain 4-(3-thiophenesulfonyloxy)-5-methoxy-7-iodoisoindolinone (0.316 g, yield 81%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19].C(N(CC)CC)C.[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH2:32][CH2:33][NH2:34])[CH3:29]>ClCCl.O>[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH2:32][CH2:33][NH:34][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19])[CH3:29]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(CCN)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(CCNc1c([N+](=O)[O-])cnc2ccccc12)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
Potassium carbonate (19.9 g, 144 mmol) was added to a mixture of 4-chloro-3-nitroquinoline (30 g, 144 mmol) and dichloromethane (150 mL). The reaction mixture was sparged with nitrogen. Triethylamine (21.8 g, 216 mmol) was added dropwise. The reaction mixture was cooled to 0° C. then a solution of 3,3-diethoxypropylamine (25.4 g, 173 mmol) in dichloromethane (50 mL) was added dropwise over a period of 15 minutes. The reaction mixture was stirred at room temperature for 3 hours. Dichloromethane and water (200 mL) were added. The layers were separated. The organic layer was washed with brine (×2). The combined aqueous layers were extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 45 g of N-(3,3-diethoxypropyl)-3-nitroquinolin-4-amine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=2)=[N:5][N:4]=[N:3]1.N1C(C)=CC=CC=1C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].Cl>ClCCl.C1(C)C=CC=CC=1>[C:26]1([O:25][C:23](=[O:24])[NH:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH:8]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cn1nnnc1-c1cccc(N)c1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reaction time: 1.5 h
Yield: 84.9 %

Procedure:
1-Methyl-5-(3-aminophenyl)-tetrazole (24.0 g, 137 mmol) was dissolved in dichloromethane (1.4 L) and 2,6-lutidine (44.1 g, 411 mmol) was added. Phenyl chloroformate (21.2 g, 136 mmol) was added in 4 portions over 15 minutes, and the mixture was stirred for 1.5 hours. The mixture was poured into 1N aqueous hydrochloric acid (200 mL) and the mixture was extracted three times with dichloromethane (200 mL). The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under vacuum to give a crude brown material. The crude brown material was dissolved in hot toluene, filtered, and allowed to precipitate at 0° C. to give a white solid (34.1 g). The filtrate was concentrated and recrystallized again from toluene to give an additional crop of off-white crystals (3.44 g, 93% total). 1H NMR (300 MHz, CDCl3), δ10.51 (bs, 1H), 8.01 (s, 1H), 7.71 (dt, J=7, 2 Hz, 1H), 7.55 (m, 2H), 7.41 (m, 2H), 7.24 (m, 2H), 4.14 (s, 3H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](Cl)=[CH:14][NH:15]2)(C)(C)C.[OH-:29].[Na+]>COC(O)C>[CH2:21]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][C:14](=[O:29])[NH:15]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N(CCOc1cccc2[nH]cc(Cl)c12)Cc1ccccc1
Agent: COC(C)O
Agent: [Na+]
Product: O=C1Cc2c(cccc2OCCNCc2ccccc2)N1
Temperature: 100 °C
Yield: 86.1 %

Procedure:
A mixture of N-benzyl-N-[2-(3-chloro-1H-indol-4-yloxy)-ethyl]-carbamic acid tert-butyl ester (5.4 g, 13.5 mmol) in methoxyethanol (25 mL) containing 85% phosphoic acid (10 mL) was heated to 100° C. for 1 hour. The reaction was allowed to cool and then basified with 2N sodium hydroxide and extracted with methylene chloride (2×150 mL). The organic layer dried over anhydrous magnesium sulfate, filtered and chromatographed (5% methanol-methylene chloride) to afford 3.28 g of a grayish-white solid (86.1%): mp 145°-146° C. The fumarate salt was prepared in isopropanol: mp 220°-221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[C:25]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:30])=[O:31])[CH:26]=[CH:27][CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: CC(C)(CO)NS(=O)(=O)c1cccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (118 mg, 0.4 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (148 mg, 0.48 mmol) (example B.6) according to general procedure II. Obtained as a yellow solid (46 mg, 22%). MS (ISP) 521.5 f (M+H)+]; mp 202–204° C.