Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]1(=[O:54])[NH:48][C:47](=[O:49])[C:46]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:45]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:48]3[C:44](=[O:54])[C:45]4[C:46](=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:47]3=[O:49])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 20 °C

Procedure:
135.0 g (417. mmol) 4-(1-diphenylmethyl-piperidin-4-yl)-butan-1-ol, 109.5 g (417 mmol) triphenylphosphine and 61.3 g (417 mmol) phthalimide are suspended in THF. Thereafter, 2.6 g (417 mmol) azodicarboxylic acid diethyl ester are added dropwise within two and a half hours under protective atmosphere and light cooling (ca. 15-25° C.). After an additional hour, the solvent is removed under vacuum and the residue is crystallized three times from acetic acid ethyl ester (1000 ml, 1200 ml and 1100 ml). Colorless crystals with an MP of 150-152° C.; yield 103 g (54.5 %).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:30]O>>[CH3:30][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:2]=1[F:1]
Reactant: CO
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Yield: 81 %

Procedure:
To 2-fluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoic acid (23, 4.0 g, 11 mmol) in 40 mL of methanol, sulfuric acid (8.8 mL, 0.16 mol) was added and the reaction mixture was refluxed overnight. The resulting reaction mixture was concentrated, and the residue was poured into 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (24, 3.35 g, 81%). MS (ESI) [M−H+]−=376.4.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[O:3].[CH3:7][C:8]([CH:10]=[CH2:11])=[CH2:9]>C(=O)([O-])O.[Na+]>[CH3:6][O:5][C:1]([C@@H:2]1[O:3][CH2:11][CH:10]=[C:8]([CH3:9])[CH2:7]1)=[O:4]
Reactant: C=CC(=C)C
Reactant: COC(=O)C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@H]1CC(C)=CCO1
Temperature: -70 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
In the same manner as in Example 1, a solution of an (R)-binaphthol-dichlorotitanium complex was obtained. This solution was cooled to -70° C. in a dry ice-acetone bath. To this solution were successively added 88 mg (1 mmole) of methyl glyoxylate and 136 mg (2 mmole) of 2-methyl-1,3-butadiene. Reaction was then allowed to proceed at -30° C. for 3 hours, and 10 ml of a sodiumhydrogen carbonate aqueous solution was added to the reaction mixture to terminate the reaction. The reaction mixture was filtered through Celite and then subjected to extraction once with a 20 ml of diethyl ether and twice with 20 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography (200 mesh; developing solvent: hexane/ethyl acetate=10/1), thereby obtaining 34 mg of desired optically active (6R)-6-methoxycarbonyl-4-methyl-5,6-dihydropyran (yield: 22%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[O-]S([O-])(=O)=O.[Ca+2].[F:12][C:13]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=1[N:23]1[C:27]2[NH:28][CH:29]=[N:30][C:31](=O)[C:26]=2[CH:25]=[N:24]1.CN(C)C=O>CC(C)=O>[Cl:3][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[N:23]([C:14]3[CH:15]=[CH:16][C:17]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:18][C:13]=3[F:12])[N:24]=[CH:25][C:26]=12
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(=O)nc[nH]c32)c(F)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Temperature: 130 °C
Yield: 89.7 %

Procedure:
POCl3 (379.1 g, 2.59 mol) was transferred under nitrogen to a 1 L round bottom flask fitted with a mechanical stirrer, a condenser and a tube connected above the condenser filled with a drying agent (drierite). 1-(2-Fluoro-4-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (4) (100 g, 0.324 mol) was added to the reaction vessel, the contents were stirred, and a slurry was obtained. Dimethylformamide (DMF; 9.43 g, 0.129 mol) was added, and the reaction mixture was heated to reflux (oil bath set at 130° C.). After refluxing for 3 h, an additional amount of DMF (9.43 g, 0.129 mol) was added. The resulting mixture was refluxed for another 2 h and then gradually cooled to 55° C. Subsequently, acetone (270 mL) was added. The mixture was further cooled to 23° C. and a precipitate was obtained, which was isolated by filtration. The filtrate was quenched by slow dropwise addition into ice water (1.5 L) with stirring. During the quench, the internal temperature was kept at 0° C. or below by cooling with an ice-salt bath. Product 4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (7) crystallized out of the quenched mixtures was isolated by filtration. The solids from both filtrations were combined and washed with water (2×500 mL), 10% aqueous NaHCO3 (2×500 mL), and water (2×500 mL) until the filtrate was neutral. The washed solids were vacuum dried overnight at room temperature and dissolved in methylene chloride (600 mL). The resulting mixture was filtered to remove any residual starting material (4). Hexane (200 mL) was added to the filtrate and methylene chloride was removed by rotary evaporation under reduced pressure. Product crystallized from the hexane solution and was filtered to obtain (7) (95 g; 90%). HPLC analysis, 99.26% (purity, by peak area); 1H NMR (Bruker 400 MHz, CDCl3) δ 8.88 (s, 1H, Ar—H), 8.46 (s, 1H, Ar—H), 7.96 (m, 3H, Ar—H), 3.14 (s, 3H, —SO2CH3); mass spec. (electrospray), m/z 327 (M+H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([CH:59]1[S:63][CH:62]([CH2:64]O)[CH2:61][CH2:60]1)[CH2:57][CH3:58]>C1COCC1>[CH2:56]([CH:59]1[S:63][CH:62]([CH2:64][O:55][C:52]2[CH:51]=[CH:50][C:49]([C:46]3[N:47]=[CH:48][C:43]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:44][N:45]=3)=[CH:54][CH:53]=2)[CH2:61][CH2:60]1)[CH2:57][CH3:58]
Reactant: CCCC1CCC(CO)S1
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCC3CCC(CCC)S3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 5-propyl-tetrahydrothiophen-2-yl-methanol (prepared by LiAIH4 reduction of methyl 5-propyl-tetrahydrothiophene-2-carboxylate). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound. The compounds (I-13) and (I-14) can be obtained in a similar manner.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7]>>[N+:6]([C:9]1[CH:10]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Temperature: 82.5 °C
Reaction time: 3 h

Procedure:
Chlorosulfonic acid (4.16 mmol, 0.475 grams) was taken in 1 L three neck round bottom flask equipped with a guard tube and liquid addition funnel. Chlorosulfonic acid was cooled in ice bath to 5-10° C. and nitrobenzene (0.83 mmol, 0.102 grams) was added to the acid slowly, at such a rate that the temperature maintained below 10° C. Reaction mixture was then brought to 25° C. and then slowly heated in an oil bath to 80-85° C. The above reaction mixture was stirred further at 80-85° C. for a period of 3 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. and poured on to the ice-water mixture under stirring, while maintaining the temperature below 10° C. The resulting slurry was then filtered on buchner funnel. The solid cake was dried on phosphorous pentoxide in a desiccator to obtain the title compound as off white solid. Yield: 0.144 grams.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][N:23]=[C:22]([NH2:25])[C:21]=2[CH:26]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][N:23]=[C:22]([NH:25][C@@H:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[C@H:3]3[OH:14])[C:21]=2[CH:26]=1
Reactant: Nc1noc2ccc(Cl)cc12
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Nc2noc3ccc(Cl)cc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 5-chloro-benzo[d]isoxazol-3-ylamine as starting materials, the title compound was prepared as a white solid.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([C:7]2[C:13]3[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=3[N:11]([CH2:22][CH3:23])[C:10](=[O:24])[CH2:9][N:8]=2)=[CH:3][CH:2]=1>[Pd].CO.C(Cl)Cl>[CH2:22]([N:11]1[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[C:7]([C:4]2[CH:3]=[CH:2][C:1]([CH2:13][CH2:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)=[CH:6][CH:5]=2)=[N:8][CH2:9][C:10]1=[O:24])[CH3:23]
Reactant: CCN1C(=O)CN=C(c2ccc(-c3ccccc3)cc2)c2cc(OC)c(OC)cc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCN1C(=O)CN=C(c2ccc(CCc3ccccc3)cc2)c2cc(OC)c(OC)cc21
Yield: 65.4 %

Procedure:
Leave the following under hydrogen pressure (Patm) for 48 hours: 80 mg of 5-(1,1′-biphenyl-4-yl)-1-ethyl-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (IIbp), 16 mg of 10% palladium on charcoal (20% by weight of product to reduce), in 30 ml of methanol and 1 ml of CH2Cl2. Filter on celite, rinse several times with methanol. Evaporate to dryness. Purify by silica chromatography (AcOEt 1/hexane 1). Recrystallize in ether. One obtains 28 mg of the abovenamed product in the form of a white powder. Yield: 35%. M: 148–150° C. 1H-NMR (CDCl3, 200 MHz): d 1.27 (t, 3H, —CH3), 3.00 (s, 4H, 2×—CH2). 3,37–3,40 (m, 2H, CH2), 3.45–3.65 (m, 4H, —OCH3+1H NCH2), 3.92 (s, 3H, OCH3), 4.21–4.48 (m, 1H, NCH2), 6.22 (d, 1H Ar), 6.77 (d, 1H Ar), 7.19–7.39 (m, 9H Ar).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[C:21]([O:23][CH3:24])=[O:22])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)C1CCCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCCC2C(=O)OC)c([N+](=O)[O-])c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a mixture of methyl 4-fluoro-3-nitrobenzoate (6.46 g, 32.5 mmole) and methyl piperidine-2-carboxylate (5.57 g, 1.2 equiv) in DMF (80 mL) was added Cs2CO3 (12.7 g). The reaction mixture was stirred at 55° C. overnight. The solid was filtered and the filtrate was evaporated. The residue was recrystallized with EtOAc/Hexane to give Methyl 1-(4-(methoxycarbonyl)-2-nitrophenyl)piperidine-2-carboxylate (9.4 g, 90%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:34][CH2:35][CH3:36])=[C:4]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:13]2[CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[O:17][C:12]=2[C:11]=1[CH2:24][CH2:25][CH3:26].S(OC)(O[CH3:41])(=O)=O.[OH-].[K+]>C1COCC1>[CH3:41][O:1][C:2]1[C:3]([CH2:34][CH2:35][CH3:36])=[C:4]([CH:27]=[CH:28][C:29]=1[C:30]([NH:32][CH3:33])=[O:31])[O:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:23]=[CH:22][C:13]2[CH2:14][CH2:15][CH:16]([C:18]([O:20][CH3:21])=[O:19])[O:17][C:12]=2[C:11]=1[CH2:24][CH2:25][CH3:26]
Reactant: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(=O)NC)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(=O)NC)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 33 (100 mg, 0.2 mmol), dimethyl sulfate (76 mg, 0.6 mmol), and potassium hydroxide (22 mg, 0.4 mmol) were added to about 15 ml of THF. The reaction mixture was stirred overnight at room temperature then washed with water and thoroughly extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Chromatography of the crude material on silica gel using 50/50 ethyl acetate/hexane as eluant gave the product.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1.[H-].[Na+].O>C(Cl)(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(NCC2CCn3c(nc4ccccc43)S2)cc1
Yield: 31 %

Procedure:
3,4-Dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in the amount of 1.12 g (3 m mole) was dissolved in 30 ml of chloroform. Then, 0.44 g of p-anisidine (3.6 m mole) and a catalytic amount of sodium hydride were added under ice-cooled stirring conditions. The temperature of the mixture was allowed to rise to room temperature, and then refluxed for 12 hours. The reaction mixture was cooled and washedwith water. After drying the chloroform layer over anhydrous magnesium sulfate, chloroform was evaporated under reduced pressure. The residue waschromatographed on silica gel and eluted with chloroform to obtain 0.28 g (yield: 31%) of the intended product, m.p. 155°-157° C.; IR νmaxKBr cm-1 : 3360, 3100-2800, 1430; Anal. Calcd. for C18H19N3OS: C, 66.44; H, 5.88; N 12.91; S, 9.85; Found: C, 66.91; H, 5.90; N, 12.88; S, 9.70.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[CH2:8]([NH2:11])[CH2:9][NH2:10].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:7][C:5]1[N:6]=[C:2]([NH:10][CH2:9][CH2:8][NH2:11])[S:3][CH:4]=1
Reactant: Cc1csc(Br)n1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1csc(NCCN)n1
Temperature: 120 °C

Procedure:
A mixture of 2-bromo-4-methylthiazole (502 mg, 2.82 mmol), ethylenediamine (15 mL, 224 mmol) and potassium carbonate (780 mg, 5.64 mmol) was heated under microwave heating at 120° C. for 30 min in a closed vial. Ethanol (200 mL) was added, the resulting mixture was filtered, the solids washed with EtOH and the combined filtrates concentrated under reduced pressure. The residue was mixed with toluene and concentrated under reduced pressure; this step was repeated two times after which 620 mg of a solid was obtained that was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]=[C:6]([C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][CH:19]=1)[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:2]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)C=Cc1c[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Product: CCOC(=O)C=C(c1ccc2cc[nH]c2c1)c1c[nH]c2ccccc12
Temperature: 114 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A sealed tube flushed with N2 was charged with 3-(1H-indol-3-yl)-acrylic acid ethyl ester (323 mg, 1.5 mmol), 6-bromoindole (196 mg, 1 mmol), tetra-butylammonium bromide (64.4 mg, 0.2 mmol), TEA (209 μl, 1.5 mmol) and palladium-dichloro-[bis(tri-ortho-tolyl)phophine] (39.3 mg, 0.05 mmol). The mixture was stirred at 114° C. for 1 hour, cooled to room temperature, dissolved in DCM, and purified via flash chromatography (hexane/EtOAc) to afford 3-(1H-indol-6-yl)-3-(1H-indol-3-yl)-acrylic acid ethyl ester XXVI (250 mg, yellow oil) as a mixture of geometric isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([F:15])[F:14])[CH:11]=1)S[CH2:7][CH2:6][C@@:5]2([C:17]([OH:19])=[O:18])[OH:16].O.O[O:22][S:23]([O-:25])=O.[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:13]([F:14])[F:15])[CH:11]=1)[S:23](=[O:25])(=[O:22])[CH2:7][CH2:6][C@@:5]2([C:17]([OH:19])=[O:18])[OH:16]
Reactant: O=S([O-])OO
Reactant: O=C(O)[C@@]1(O)CCSc2c(OC(F)F)cc(Cl)cc21
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)[C@@]1(O)CCS(=O)(=O)c2c(OC(F)F)cc(Cl)cc21
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of (R)-6-chloro-8-difluoromethoxy-4-hydroxythiochromane-4-yl-carboxylic acid (0.50 g, 1.6 mmol; from step (vi) above), wet alumina (prepared by adding H2O (1 mL) to alumina (5.0 g) and shaking until a free flowing powder was obtained, ca. 0.82 g, 8.0 mmol), and Oxone® (4.9 g, 8.0 mmol) in CHCl3 (19 mL) was heated to 40-45° C. for 20 h. The reaction was cooled to room temperature, filtered through a Buichner funnel with EtOAc (50 mL), and concentrated in vacuo to afford 0.54 g (98%) of the sub-title compound as a brown foam which was used without further purification.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:5]([C:20]#[N:21])[C:4]1=[O:22].[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].CCN(C(C)C)C(C)C>ClCCl>[C:23]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]([CH3:2])[C:4](=[O:22])[C:5]=2[C:20]#[N:21])[CH2:19][CH2:18]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: Cn1c(=O)c(C#N)c(NC2CCNCC2)c2ccccc21
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCC(Nc2c(C#N)c(=O)n(C)c3ccccc23)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-Methyl-2-oxo-4-(piperidin-4-ylamino)-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (leg, 0.020 g, 0.07 mmole) in dichloromethane at −10° C. was added acryloyl chloride (1.1 eq, 0.007 g, 0.077 mmole) followed by the addition of N,N′-diisopropylethylamine (1.5 eq, 0.014 g, 0.011 mmole, 0.02 mL). The resulting solution stirred at −10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-(1-Acryloyl-piperidin-4-ylamino)-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.004 g, 32% calc M+H 337, obs M+H 337).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:6]([C:8]1[N:13]([CH2:14][C:15]2([CH2:18][C:19](O)=[O:20])[CH2:17][CH2:16]2)[C:12](=[O:22])[NH:11][C:10](=[O:23])[C:9]=1[CH:24]([CH3:26])[CH3:25])=[O:7])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>C1COCC1.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:6]([C:8]1[N:13]([CH2:14][C:15]2([CH2:18][C:19]([NH:44][CH2:43][C:42]3[CH:45]=[CH:46][C:39]([O:38][CH3:37])=[CH:40][CH:41]=3)=[O:20])[CH2:16][CH2:17]2)[C:12](=[O:22])[NH:11][C:10](=[O:23])[C:9]=1[CH:24]([CH3:26])[CH3:25])=[O:7])#[N:2]
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC2(CC(=O)O)CC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)CC2(Cn3c(C(=O)c4cc(C)cc(C#N)c4)c(C(C)C)c(=O)[nH]c3=O)CC2)cc1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a stirred solution of {1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-acetic acid (90 mg, 0.22 mmol) in THF (5 mL) cooled in an ice bath, were added oxalyl chloride (38 μL, 0.44 mmol) and one drop of DMF. After stirring for 1 hr., the mixture was evaporated in vacuo. The residue was dissolved in THF (8 mL) and p-methoxy benzylamine (261 μL, 2 mmol) was added. After stirring for 1 hr., the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (2:1): Rf=0.25 fraction was collected) to give 97 mg (83%) of 2-{1-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-cyclopropyl}-N-(4-methoxy-benzyl)-acetamide (84) as a white solid. 1H-NMR (200 MHz, CDCl3) δ 0.40-0.46 (4H, m), 1.12 (3H, d, J=6.6 Hz), 1.23 (3H, d, J=6.6 Hz), 2.00 (1H, d, J=15.4 Hz), 2.25 (1H, m), 2.48-2.55 (4H, m), 3.45 (1H., d, J=15.4 Hz), 3.80 (3H, s), 3.90 (1H, d, J=15.4 Hz), 4.34-4.39 (2H, m), 6.69 (1H, m), 6.83-6.90 (2H, m), 7.22-7.30 (2H, m), 7.81 (1H, s), 8.01 (1H, s), 8.07 (1H, s), 9.81 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2Br)[CH:7]=[C:6]([NH2:16])[CH:5]=1.[F:18][C:19]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:20]=1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([NH2:16])[CH:7]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[C:24]2[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21][C:20]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:19]=2[F:18])[CH:9]=1
Reactant: OB(O)c1cc(Br)ccc1OCc1ccc(F)cc1F
Reactant: COC(=O)c1cc(N)cc(C2=C(Br)CCC2)c1
Product: COC(=O)c1cc(N)cc(C2=C(c3cc(Br)ccc3OCc3ccc(F)cc3F)CCC2)c1

Procedure:
Prepared by general procedure 3 but using 3-amino-5-(2-bromocyclopent-1-enyl)benzoic acid methyl ester instead of 3-(2-bromocyclopent-1-enyl)benzoic acid ethyl ester and 2-(2,4-difluorobenzyloxy)-5-bromophenylboronic acid instead of 5-chloro-2-methoxyphenylboronic acid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH2:19][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Product: c1cc(N2CCC(CN3CCCCC3)CC2)ccc1CN1CCCC1

Procedure:
Prepared from the product of Example 16 and piperidine.