Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=1.[NH2:12][C:13]1[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=[C:15]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH2:28]2)[N:14]=1.N1C=CC=CC=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:11])[C:8]([NH:12][C:13]2[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=[C:15]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:34])[CH2:28]3)[N:14]=2)=[O:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: C[C@H](C(=O)O)n1cc(Cl)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@H](C(=O)Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)OC(C)(C)C)n1cc(Cl)cn1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
(R)-2-(4-Chloro-1H-pyrazol-1-yl)propanoic acid (105 mg, 0.60 mmol) and (R)-tert-butyl 2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamate (195 mg, 0.50 mmol) were dissolved in ethyl acetate (0.5 mL) with pyridine (0.20 mL, 2.5 mmol) at room temperature. The mixture was cooled to 0° C. 1-Propanephosphonic acid cyclic anhydride (0.375 mL, 50% solution in ethyl acetate, 1.25 mmol) was added while stirring at 0° C. The resulting mixture was stirred for 15 min, and then warmed to room temperature. After stirring for 1.5 h at room temperature, the mixture was quenched with an aqueous solution of hydrochloric acid (0.5 M, 1 mL). The mixture was partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was washed sequentially with water (5 mL), a saturated aqueous solution of sodium bicarbonate (5 mL), and brine (5 mL). The organics were dried over magnesium sulfate, filtered, and concentrated. The residue was dried under reduced pressure to afford tert-butyl 2-((R)-2-(4-chloro-1H-pyrazol-1-yl)propanamido)-6-((R)-3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamate (268 mg, 98% yield). 1H NMR (500 MHz, CDCl3) δ 1.48 (s, 9H), 1.48-1.55 (m, 1H), 1.73-1.76 (m, 1H), 1.80-2.05 (m, 6H), 1.86 (d, 3H), 2.53-2.59 (m, 1H), 2.84-2.90 (m, 1H), 2.96-3.01 (m, 1H), 3.43-3.51 (m, 3H), 3.55-3.60 (m, 1H), 4.12 (br d, 1H), 4.33 (br d, 1H), 5.10 (br s, 1H), 6.56 (d, 1H), 7.30 (br s, 1H), 7.57 (s, 1H), 7.61 (s, 1H), 7.76 (br s, 1H), 8.58 (br s, 1H); MS (ES+) (M+H) 546.3; Chiral HPLC retention time 4.61 min (Method: Chiralpak AS-H 0.46×25 cm; Mobile Phase: CO2/methanol; Flow: 2.5 mL/min); 97.1% de.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:21])[S:11]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][C:15]=2Cl)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:21])[S:11]([C:14]2[CH:18]=[C:17]([Cl:19])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(CCc1ccc(F)cc1)S(=O)(=O)c1cc(Cl)sc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc(Cl)c1
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of 2,5-dichlorothiophene-3-sulfonic acid [2-(4-fluorophenyl)ethyl]-methyl-amide (1.14 g) in tetrahydrofuran (10 mL) was added dropwise a solution of 1.59M n-butyl lithium-hexane (2.3 mL) on an ice bath. After stirring for 30 minutes, an aqueous solution of saturated ammonium chloride was poured. After diluting with water, the solution was extracted with ethyl acetate. After the organic layer was washed with saturated sodium chloride water, and was dried with anhydrous sodium sulfate. The residue that was obtained upon removing the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (pale yellow oily substance) (939 mg) was obtained (contains impurities).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH:5]=O.[C:18]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH2:18])[CH:7]=[CH:8][C:9]=1[CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(CNc2ccccn2)c(Cl)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(CNc2ccccn2)c(Cl)c1
Temperature: 100 °C
Yield: 50.4 %

Procedure:
To a stirred solution of 3-chloro-4-((pyridin-2-ylamino)methyl)benzaldehyde (1 g, 4. mmol) in 1,4-dioxane (20 mL) were added K2CO3 (0.84 g, 6.09 mmol) and methyl triphenyl phosphonium bromide (2.17 g, 6.09 mmol) at ambient temperature. Then the resultant reaction mixture was heated at 100° C. for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 10% EtOAc in n-Hexane) to afford the title compound as a white solid (0.5 g, 50%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.42-7.40 (m, 3H), 7.26 (s, 1H), 6.66 (m, 2H), 6.36 (d, J=6.3 Hz, 1H), 5.75 (d, J=13.2 Hz, 1H), 4.92 (br s, 1H), 4.60 (s, 2H); ESIMS m/z 245.05 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.C(Cl)(Cl)Cl.[O:28]1CCOCC1>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][O:28][CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: C1COCCO1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccccc2)=NCC1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCC1COCCN21

Procedure:
A solution of 20 g 7-chloro-1-(β-chloroethyl)2-chloromethyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine in 100 ml dioxane and 250 ml of 6% sodium hydroxide solution is heated under reflux for a period of about 5.5 hours. After heating the solution, the substance is isolated from chloroform under vacuum and subsequently purified chromatographically using aluminum oxide (activity degree II) as absorbent and methylene chloride as eluant. 12.8 g 1,2,4,4a-tetrahydro-9-chloro-7-phenyl-5H[1,4]oxazino-[4,3-a][1,4]benzodiazepine as an oil is obtained. The maleanate having a melting point of 143° to 145° C. is crystallized from isopropanol/ether. The basic compound crystallized from hexane melts at 156°-158° C.
Reaction SMILES: C(N1C(C2SC3N=CN=C(SC)C=3C=2)=C(C2C=CC=CC=2)N=C1)C.[CH2:25]([N:27]1[C:31]([C:32]2[S:33][C:34]3[N:35]=[CH:36][N:37]=[C:38]([S:41][CH3:42])[C:39]=3[N:40]=2)=[C:30]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=[CH:28]1)[CH3:26].CSC1C2C=C(C=[O:61])SC=2N=CN=1.C(CN)O>>[CH3:42][S:41][C:38]1[C:39]2[N:40]=[C:32]([C:31]3[N:27]([CH2:25][CH2:26][OH:61])[CH:28]=[N:29][C:30]=3[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[S:33][C:34]=2[N:35]=[CH:36][N:37]=1
Reactant: CSc1ncnc2sc(C=O)cc12
Reactant: CCn1cnc(-c2ccccc2)c1-c1nc2c(SC)ncnc2s1
Agent: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Solvent: NCCO
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3CCO)nc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 70 but using 7-(methylthio)[1,3]thiazolo[5,4-d]pyrimidine-2-carbaldehyde (Intermediate 78) in place of 4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (Intermediate 15) and ethanolamine in place of ethylamine. Colourless solid (52 mg, 56%);
Reaction SMILES: C(NCC)C.Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].[C:16](#[N:20])[CH2:17][C:18]#[N:19]>CN(C=O)C>[NH2:20][C:16]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:17]=1[C:18]#[N:19]
Reactant: N#CCC#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccccc2)oc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add 68.6 ml (663 mmol) diethylamine dropwise to a mixture of 60.0 g (301 mmol) bromoacetophenone and 25.89 g (391.86 mmol) malononitrile in 130 ml DMF at RT (cooling is required to maintain the temperature). Towards the end of addition, remove the cooling, stir the mixture for 1 h at RT and then add water to 385 ml. Dilute with a further 125 ml water and stir for 20 min at RT. Filter off the precipitated solids with suction, wash twice with 125 ml water each time, dry under suction and wash with petroleum ether. Dry the residue at high vacuum. 33.3 g (50.1% of theor.) of the target compound is obtained as yellowish-brown crystals.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].CN(C)CCN(C)C.[CH3:20][O:21][C:22]1[C:23]([O:32][CH2:33][O:34][CH3:35])=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=[O:26]>O1CCCC1>[CH3:23][O:32][CH2:33][O:34][C:8]1[CH:7]=[CH:6][CH:11]=[CH:10][C:9]=1[CH:25]([C:24]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:22]([O:21][CH3:20])[C:23]=1[O:32][CH2:33][O:34][CH3:35])[OH:26]
Reactant: COCOc1c(C=O)ccc(OC)c1OC
Reactant: CCCCCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccccc1C(O)c1ccc(OC)c(OC)c1OCOC
Temperature: 0 °C
Yield: 200.1 %

Procedure:
A 1.6M solution of butyl lithium in hexane (91 ml, 146 mmol) was placed in an oven-dried 500 ml 3-necked flask and cooled to 0° C. and then 22.5 ml (20.1 mmol) of tetramethylethylenediamine was added with stirring. After a 10 min reaction period, a solution of 18.3 g (133 mmol) of methoxymethoxybenzine was added and the mixture allowed to stir for about 3.5 hours at 0° C. 3,4-Dimethoxy-2-methoxymethoxybenzaldehyde (30.0 g, 133 mmol) in 18 ml of tetrahydrofuran was then added dropwise with stirring. The mixture was allowed to warm to room temperature and stir for 1 hour and was then quenched with 50 ml of saturated aqueous ammonium chloride. The resulting mixture was extracted with 200 ml of ethyl acetate three times. The combined extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 48.5 g of an oil. This was purified by silica gel chromatography on an 8 in. diameter sintered glass funnel eluting with mixtures of hexane and dichloromethane increasing from 38 percent to 75 percent dichloromethane to obtain 32.2 g (68 percent of theory) of the title compound as a yellow oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(Cl)(Cl)(Cl)[Cl:43]>>[CH2:1]([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:11][Cl:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1[C@@H](CO)COCc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: COc1ccccc1[C@@H](CCl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (2S)-3-benzyloxy-2-(2-methoxyphenyl)propan-1-ol (Description 98, 2 g, 7.4 mmol) and triphenylphosphine (2.12 g, 8.1 mmol) in carbon tetrachloride (10 mL) was heated in an oil bath at 100° C. for 5 h. Methanol (1 mL) was cautiously added and the mixture was cooled to room temperature and stirred for 16 h. The solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel, eluting with hexane/EtOAc (100:0 increasing to 95:5) to give the title compound (1.5 g). 1H NMR (250 MHz, CDCl3) δ7.37-7.2 (7 H, m), 6.96-6.86 (2 H, m), 4.54 (2 H, s), 3.92 (2 H, m), and 3.81-3.73 (7 H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[C:22]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:23]([O:26][CH3:27])=[N:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 31.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxypyridin-3-yl) methanesulfonamide (70 mg, 0.108 mmol) was hydrolyzed with lithium hydroxide (14 mg, 0.324 mmol) in THF/methanol/water (3.5/3.5/0.5 mL) to yield 17 mg (31.8% yield) after purification by preparative TLC (Silicagel-1000 micron) using 5% methanol in chloroform as eluent. 1H NMR (CD3OD, 300 MHz): δ 8.42 (s, 1H), 8.34-8.33 (s, 1H), 8.288-8.280 (d, 1H), 8.22 (s, 1H), 8.04-8.03 (d, 1H), 7.934-7.931 (d, 1H), 8.04-8.03 (d, 1H), 7.934-7.931 (d, 1H), 7.65 (s, 1H), 7.38-7.35 (q, 1H), 7.12-7.09 (d, 1H), 7.03-6.99 (m, 2H), 5.42 (s, 2H), 4.06 (s, 3H), 3.03 (s, 3H). MS: m/z=492.8 (M+1), HPLC: 96.33% in method B.
Reaction SMILES: [O:1]=[S:2]1(=[O:12])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20](O)=[C:21]([C:24]#[N:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:11][CH2:10][CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:12])[CH2:3][CH2:4]3)=[C:21]([C:24]#[N:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1
Reactant: O=S1(=O)CCN(CCCO)CC1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
3-(1,1-Dioxothiomorpholino)propan-1-ol (283 mg, 1.46 mmol) was added to a suspension of 4-chloro-6-cyano-7-hydroxyquinoline (200 mg, 0.97 mmol) in methylene chloride (30 ml), followed by the addition of triphenylphosphine (512 mg, 1.95 mmol) and a solution of diethyl azodicarboxylate (310 μl, 1.95 mmol) in methylene chloride (700 μl) in portions. After stirring for 5 minutes at ambient temperature, the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with a mixture of methanol/ethyl acetate/methylene chloride (5/50/45). After combining the fractions containing the expected product, the solvents were removed under vacuum and the residue was triturated with methanol, collected by filtration, washed with methanol and dried under vacuum to give 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (321 mg, 87%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21]2)[CH2:17][CH2:16]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21]4)[CH2:17][CH2:16]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC2(C=Cc3ccccc32)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and spiro[1H-indene-1,4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. mp 119°-120°. FDMS m/e=374 (M+ of free base). α[D]589 =-5.51 (c=0.47, methanol).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[CH3:10][C:11]1[C:12](=[O:31])[C:13]([C:27](OC)=[O:28])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:16]=1>ClCCl>[CH3:5][O:4][N:3]([CH3:2])[C:27]([C:13]1[C:12](=[O:31])[C:11]([CH3:10])=[CH:16][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)[N:14]=1)=[O:28]
Reactant: COC(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1nn(-c2cccc(C(F)(F)F)c2)cc(C)c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (0.468 g, 4.8 mmol) in dichloromethane (5 mL) was added trimethylaluminum (2.4 mL, 4.8 mmol, 2 M solution in toluene) dropwise at 0° C. Following addition, the suspension was stirred at 0° C. for 10 min then at room temperature for 30 min to provide a homogenous solution. The flask was then re-cooled in an ice bath. In a separate flask, methyl 5-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxylate (0.500 g, 1.6 mmol) was dissolved in dichloromethane (5 mL) and added dropwise and allowed to stir for 2 h. The reaction was quenched with water (5 mL) and 2 N HCl aqueous solution (2 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered and concentrated to provide N-methoxy-N,5-dimethyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (0.535 g, 98%) as a yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:14]2[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][NH:15]2)[CH:6]=[C:7]([F:13])[C:8]=1[C:9]([F:12])([F:11])[F:10].CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:36])[O:34][CH3:35]>C(Cl)Cl>[F:13][C:7]1[CH:6]=[C:5]([CH:14]2[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]2[C:33]([O:34][CH3:35])=[O:36])[CH:4]=[C:3]([F:2])[C:8]=1[C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)C1CCNC(c2cc(F)c(C(F)(F)F)c(F)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (3.118 g, 8.67 mmol) and DIPEA (3.02 mL, 17.34 mmol) were dissolved in DCM (30 mL). Methyl carbonochloridate (1.024 mL, 13.00 mmol) was added and the reaction stirred at room temperature for 1.5 h. Additional methyl carbonochloridate (0.341 mL, 4.33 mmol) was added and stirring continued for 0.5 h. DCM (170 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo to yield dimethyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-piperidine-1,4-dicarboxylate (2.85 g, 86%) as a colorless oil. MS m/z 382 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH:37]([NH:40][CH2:41][CH2:42][NH2:43])([CH3:39])[CH3:38].C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([NH:43][CH2:42][CH2:41][NH:40][CH:37]([CH3:39])[CH3:38])=[O:29])[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1
Reactant: CC(C)NCCN
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCNC(C)C)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and N-isopropylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 593.16 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2Br)=[CH:5][CH:4]=1.[N+:19]([O-:24])([N+]([O-])=O)=[O:20].C1CCC(C(O)=O)CC=1>C(O)(=O)C>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[N+:19]([O-:24])=[O:20])=[CH:5][CH:4]=1
Reactant: BrCc1ccc(-c2c(Br)oc3ccccc23)cc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C(O)C1CC=CCC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1oc2ccccc2c1-c1ccc(CBr)cc1

Procedure:
Starting with 3-(4'-bromomethyl phenyl)-2-bromobenzofuran, nitration with dinitrogen tetraoxide in acetic acid in the presence of cyclohexene-4-carboxylic acid provides 3-(4'bromomethyl phenyl)-2-nitrobenzofuran which is reacted according to the method of Example 1 with N,N'-dimethylaminoethylamine. The product obtained is 3-[4'-(N,N'-dimethylaminoethylaminomethyl)phenyl]-2-nitrobenzofuran having the structure ##STR35##
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=O)[C:4]=2[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1([NH2:27])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16]([C:18]1([NH:27][C:10]([C:5]2[C:4]3[CH:3]=[CH:2][NH:1][C:9]=3[CH:8]=[CH:7][CH:6]=2)=[O:12])[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3[nH]ccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a solution of 1H-indole-4-carboxylic acid (250 mg, 1.55 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-60% EtOAc in heptane) to give a pure product (55) as white solid (278 mg, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].N1CCCCC1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOc1ccc(/C=C/C(=O)O)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A solution of 4-ethoxybenzaldehyde (1.00 mL, 7.20 mmol) and piperidine (0.11 mL, 1.08 mmol) in 40 mL of pyridine was heated to 120° C. A solution of malonic acid (1.50 g, 14.40 mmol) in 40 mL of pyridine was added dropwise over 30 min and the reaction solution was stirred at 120° C. for 4 h. After cooling down to 0° C., excess amount of concentrated HCl was added carefully to make ˜pH 1. A white crystalline precipitate formed, and the solid was collected by filtration, washed with 0.1 N HCl aqueous solution, and dried to afford compound 19 in 99.5% (1.40 g) of pure 19 as a white solid.