Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[C:30]([O:34][C:35]([N:37]1[CH2:44][C@@H:43]([OH:45])[CH2:42][C@H:38]1[C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[C:30]([O:34][C:35]([N:37]1[CH2:44][C@H:43]([OH:45])[CH2:42][C@H:38]1[C:39]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:40])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
17.16 g (62.40 mmol) of diphenylphosphoryl azide, 5.70 g (78.08 mmol) of t-butylamine and 10.4 g (104.00 mmol) of triethylamine were added, in that order, to a solution of 12.0 g (51.95 mmol) of (4S)-1-t- butoxycarbonyl-4-hydroxy-L-proline in 100 ml of dimethylformamide, whilst ice-cooling, and the mixture was stirred for 5 hours. At the end of this time, the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with a 10% w/v aqueous solution of citric acid, with a 10% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which the mixture was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was recrystallized from ethyl acetate, to give 10.0 g of the title compound as colorless crystals, melting at 192°-193° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:17]=1>>[CH2:25]([O:24][C:18]1[CH:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=1[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCCCOc1cc(Cl)ccc1CO
Product: CCCCOc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-butoxyphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.95 (3H, t, J=7.2 Hz), 1.41-1.48 (2H, m), 1.74-1.79 (2H, m), 4.01 (2H, t, J=6.4 Hz), 5.23 (2H, s), 5.77 (1H, d, J=1.6 Hz), 6.90 (1H, d, J=2.0 Hz), 6.95 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.34 (1H, d, J=8.0 Hz), 7.39 (1H, dd, J=0.8 Hz, 4.8 Hz), 7.57 (1H, d, J=1.6 Hz), 8.04 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H19ClN4O2, 383. Found, 383.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([CH2:12][C:13]#[N:14])[C:9]([CH2:15][CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]([C:22]1[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=1[CH3:29])=O)C.CCCCCCC.CC(C)([O-])C.[K+]>COCCOCCOC>[C:1]1([N:7]2[N:11]=[C:10]([CH:12]([C:20]([C:22]3[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=3[CH3:29])=[O:19])[C:13]#[N:14])[C:9]([CH2:15][CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCc1nn(-c2ccccc2)nc1CC#N
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: COCCOCCOC
Product: CCc1nn(-c2ccccc2)nc1C(C#N)C(=O)c1c(C)c(C)nn1C
Temperature: 92.5 °C
Yield: 68 %

Procedure:
In a 2 L-reaction flask equipped with a rectification column, 106 g (0.5 mol) of 2-phenyl-4-cyanomethyl-5-ethyl-1,2,3-triazole, 91 g (0.5 mol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 530 g of heptane, and 106 g of diethylene glycol dimethyl ether were added, then azeotropic dehydration was carried out by heating at 90 to 95° C. Thereafter 61.7 g (0.55 mol) of potassium-tert-butoxide was carefully added under nitrogen atmosphere, then the resulting solution was heated at 95° C. and reacted for 15 hours while removing the eluent from the rectification column. After cooling to 30° C. or less, 3000 g of water was added to separate out heptane phase, and the resulting aqueous phase was further washed with 600 g of heptane to separate into phases. A quantitative analysis of the obtained aqueous phase with liquid chromatography showed that the aqueous phase contained 118.5 g (yield 68%) of 2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile. The aqueous solution was warmed at 40° C., pH was adjusted to 1 by adding 35% hydrochloric acid with stirring. The crystal obtained by cooling to 15° C. over 2 hours was filtered. The crystal cake was washed three times with 200 ml of water and then dried to obtain 116 g (yield 66.5%) of 2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethyl-5-pyrazolyl)-3-oxopropionitrile (melting point 119° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:14]C2N=NC=CC=2C=1O)=[O:5])[CH3:2].C(O[C:19](=[O:28])[C:20]1[C:25](Br)=[CH:24][N:23]=[C:22]([Cl:27])[CH:21]=1)C>>[CH2:1]([O:3][C:4]([C:6]1[O:14][C:25]2=[CH:24][N:23]=[C:22]([Cl:27])[CH:21]=[C:20]2[C:19]=1[OH:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2nnccc2c1O
Reactant: CCOC(=O)c1cc(Cl)ncc1Br
Product: CCOC(=O)c1oc2cnc(Cl)cc2c1O

Procedure:
This compound was prepared using a method analogous to that of 5-hydroxyfuro[2,3-c]pyridazine-6-carboxylic acid ethyl ester (A.2.3.1), 5-bromo-2-chloroisonicotinic acid ethyl ester replacing 3-chloropyridazine-4-carboxylic acid ethyl ester. Purification by CC (KP-SIL™ from Biotage) using EtOAc/MeOH (9/1) gives the desired product as brown solid;
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.CCOC(OC(OCC)=O)=O.[NH2:26][C:27]1[C:35]2[O:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:26][C:27]2[C:35]3[O:34][C:33](=[O:36])[NH:32][C:31]=3[CH:30]=[CH:29][CH:28]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Reactant: Nc1cccc2[nH]c(=O)oc12
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1cccc2[nH]c(=O)oc12
Temperature: 80 °C
Yield: 46 %

Procedure:
4-trifluoromethylphenylacetic acid (453 mg, 2.2 mmol) was dissolved in 20 ml of THF and at 0° C. DEPC (0.43 ml, 1.3 equiv) and amine 1c (400 mg, 2.66 mmol) were added to the solution. The mixture was warmed at 80° C. overnight, then evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 3/petroleum ether 7 as eluant gave 340 mg of a white solid. Yield=46% 1HNMR (DMSO, 200 MHz) δ 3.86 (2H, s), 6.86 (1H, d), 7.06 (1H, t), 7.58 (3H, m), 7.70 (2H, d, J=8.4 Hz), 10.32 (1H, bs), 8.73 (1H, bs), 11.80 (1H, bs); [M+1] 337.2 (C16H11F3N2O3 requires 336.3).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:21]([O:23]N1C(=O)CCC1=O)=O)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])[CH3:3].[NH:31](C(OC(C)(C)C)=O)[C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH:47][NH:48][C:49]([O:51][CH2:52][C:53]([Cl:56])([Cl:55])[Cl:54])=[O:50])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[C@H:33]([CH2:35][CH3:36])[CH3:34]>C1COCC1.C(OCC)(=O)C>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:21]([NH:31][C@H:32]([C:37]([NH:39][C@H:40]([C:45]([NH:47][NH:48][C:49]([O:51][CH2:52][C:53]([Cl:54])([Cl:55])[Cl:56])=[O:50])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:38])[C@H:33]([CH2:35][CH3:36])[CH3:34])=[O:23])[CH2:10][C:11](=[O:12])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Reaction time: 4 h

Procedure:
The preceding 30 g of oil in solution in 250 ml of THF are treated with 6.4 ml (50 mM) of NEM and 18.9 (45 mM) of Boc-Asp(OBzl)O Su. The apparent pH is adjusted between 6 and 7 by successive additions of NEM. After 4 hours, the product is isolated by evaporation of the THF, take-up in 400 ml of ethyl acetate followed by the same washings as the preceding homologue (3). The residue after drying and evaporation (36.5 g) is purified by chromatography over a column of silica with dichloromethane as solvent containing from 0 to 1.5% of methanol. 25 g (66%) of product presenting an NMR spectrum in accordance with the expected structure are thus obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]#[N:16])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15]3[NH:24][C:23]4[C:18]([N:16]=3)=[N:19][CH:20]=[CH:21][CH:22]=4)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CC1CCCN(Cc2ccccc2)CC1
Reactant: Nc1cccnc1N
Product: c1ccc(CN2CCCC(c3nc4ncccc4[nH]3)CC2)cc1
Temperature: 180 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
Polyphosphoric acid (PPA) (10 g) was heated to 160° C. Intermediate (1) (0.0467 mol) and 2,3-diaminopyridine (0.0513 mol) were added. The mixture was stirred at 180° C. for 1 hour, poured out on K2CO3 solid and ice, washed with K2CO3 10% and extracted with DCM. The aqueous layer was washed with DCM. The organic layer was dried, filtered and the solvent was evaporated.This fraction was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 94/6/0.5). The pure fractions were collected and the solvent was evaporated. Part of this fraction (6 g) was crystallized from DIPE and 2-propanone. The precipitate was filtered off and dried, yielding 3.16 g of (±)-2-[hexahydro-1-(phenylmethyl)-1H-azepin-4-yl]-1H-imidazo[4,5-b]pyridine (compound 69).
Reaction SMILES: C(O[C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:32]=[CH:31][CH:30]=[CH:29]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[N:10]=1)=[O:5])C.[NH2:34][CH2:35][CH2:36][OH:37]>>[OH:37][CH2:36][CH2:35][NH:34][C:4]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH2:18][C:19](=[O:33])[NH:20][C:21]4[CH:27]=[C:26]([N:28]5[CH:29]=[CH:30][CH:31]=[CH:32]5)[CH:25]=[CH:24][C:22]=4[N:23]=3)[CH:12]=2)[N:10]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1nc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)cs1
Product: O=C1CC(c2cccc(-c3csc(C(=O)NCCO)n3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
A sample of 4-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-thiazole-2-carboxylic acid ethyl ester (Example 28) (0.26 g) was reacted with 2-amino-ethanol in an analogous manner to the procedure described in Example 34 to give the title compound (0.07 g) as a light-yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][S:20]([CH3:19])(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-nitro-phenyl)-ethanol (1 eq) in dichloromethane at 0° C. was added pyridine (4 eq) and methanesulfonyl chloride (2 eq). After stirring at 0° C. for one hour, then room temperature overnight, the mixture was diluted with dichloromethane and washed once with water, once with 1 N HCl, dried with anhydrous sodium sulfate, filtered and concentrated. The product was clean enough to be taken on to the next step without purification. MH+=246.0.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17]
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1cc2ccccc2c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Under an argon atmosphere, 25.7 g of 9-bromophenanthrene, 16.5 g of 2-formylphenylboronic acid and 2.31 g of tetraxis(triphenylphosphine)palladium(0) were placed in a flask. 340 mL of dimethoxyethane (DME) and 170 mL of a 2M aqueous sodium carbonate solution were added to this flask, and the resultant was refluxed with stirring while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The residue was purified by means of silica gel column chromatography, whereby 25.0 g (yield: 89%) of intended 9-(2-formylphenyl)phenanthrene was obtained.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[F-].[Cs+].[CH3:8][O:9][C:10](=[S:32])[NH:11][CH2:12][C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)=[C:20]([F:31])[CH:19]=2)[CH:17]=1>C(O)C.C(OCC)(=O)C>[CH3:8][O:9][C:10](=[S:32])[NH:11][CH2:12][C:13]1[N:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][C:27](=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:26][CH2:25]3)=[C:20]([F:31])[CH:19]=2)[CH:17]=1
Reactant: COC(=S)NCc1cn(-c2ccc(N3CCC(=O)CC3)c(F)c2)nn1
Reactant: N#CCC#N
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=S)NCc1cn(-c2ccc(N3CCC(=C(C#N)C#N)CC3)c(F)c2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of malononitrile (22 mg, 0.33 mmol) and CsF (42 mg, 0.28 mmol) in ethanol (5 ml) was added {1-[3-Fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-1H-[1,2,3]triazol-4-ylmethyl}-thiocarbamic acid O-methyl ester (100 mg, 0.28 mmol), obtained in Example 82. The reaction mixture was allowed to stir at room temperature for 2 h and then diluted with ethyl acetate (100 ml). The organic portion was washed with water followed by brine and dried over sodium sulfate. Removal of volatiles and purification of the resulting residue by silica gel column chromatography (ethyl acetate/pet. ether, 1:1), the title compound was obtained as white solid (45 mg, 40%). Mp. 198° C.
Reaction SMILES: [CH2:1]([CH:3]([C:14](OCC1C=CC=CC=1)=[O:15])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[CH3:2]>CCCCCC.CCOC(C)=O>[CH:14]([CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])=[O:15]
Reactant: CCC(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(C=O)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from ethylmalonic acid, dibenzyl ester (from Step A) using a procedure analogous to that described for Aldehyde 3, Step B. RF: 0.35 (9:1 v/v hexane/EtOAc); 1H-NMR (500 MHz: Equilibrium mixture of aldehyde and enol) δ 0.92–1.00 (m), 1.04–1.08 (m), 1.93–2.01 (m), 2.14–2.18 (m), 5.17, 5.23, 5.26 (3s), 7.05 (d, J=12.6), 7.30–7.41 (m), 9.74 (d, J=2.3), 11.33 (d, J=12.6).
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:5]1[N:10]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[C:9](=[O:11])[CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C2CC2)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1nc(C2CC2)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 43.7 %

Procedure:
To a solution of 2-butyl-6-cyclopropylpyrimidin-4(3H)-one (6 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (9.34 g) in acetonitrile (180 mL) was added potassium carbonate (8.63 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (5.23 g, 44%) as a colorless viscous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[Br-].O=[C:14]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C:17]1=[N+]1CCCC1>CO.C(#N)C>[C:7]([C:6]1[CH:10]=[C:2]([N:1]2[C:17]3[CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:16]=3[CH:15]=[C:14]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=[CH:4][C:5]=1[OH:11])([OH:9])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C(CC1C(=[N+]2CCCC2)CCc2ccccc21)c1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: CC#N
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O

Procedure:
A mixture of 1.92 g of 5-aminosalicylic acid and 5.0 g of tautomeric 1-[3,4-dihydro-1-(2-oxo-2-phenylethyl)-2(1H)-naphthalenylidene]pyrrolidinium bromide in equilibrium with 1-phenacyl-2-(1-pyrrolidino)-3,4-dihydronaphthalene hydrobromide (Example 1a), in 75 ml of methanol is refluxed under nitrogen for 9 hours. The solution is allowed to reach ambient temperature before being filtered. The methanol is removed under a vacuum to give a viscous oil which is dissolved in acetonitrile. This solution immediately crystallizes to give a yellow crystalline solid which is collected by filtration and washed with acetonitrile to give 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole.
Reaction SMILES: [CH:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][N:16]([CH3:31])[CH2:17][CH2:18][N:19]([CH3:30])[C:20]1[S:21][C:22]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=2[N:24]=1>>[CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:29][C:27]3[CH:26]=[CH:25][C:23]4[N:24]=[C:20]([N:19]([CH2:18][CH2:17][N:16]([CH3:15])[CH3:31])[CH3:30])[S:21][C:22]=4[CH:28]=3)=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(C2CCCC2)cc1
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(C4CCCC4)cc3)cc2s1

Procedure:
The title compound is prepared by following General Method A, using 4-cyclopentyl-benzoic acid (0.099 g, 0.52 mmol), and N*2*-(2-Dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (0.10 g, 0.40 mmol) to give 0.38 g (23%) of product. LC/MS: Retention time=4.97 min; (m/z): calcd for C24H30N4OS (M+H)+: 423.6; found: 423.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:15])[CH2:13][OH:14])([CH3:4])([CH3:3])[CH3:2].[CH:17](=O)[CH:18]([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:15][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:13][OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C=O
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)CO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN[C@H](CO)CCCCNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 31 %

Procedure:
(S)-(5-Amino-6-hydroxy-hexyl)-carbamic acid tert-butyl ester (3) (6.85 g) was dissolved in 200 mL CH2Cl2. Isobutyraldehyde (2.67 mL) was added and this solution was stirred for 2 hours. Sodium triacetoxyborohydride (1.1 eq) was added and the solution was stirred for 2 hours at RT. The solution was washed with sat. NaHCO3. The milky organic phase was separated and evaporated to dryness. The residue was purified by column chromatography using 99:1 EtOAc (100%) to EtOAc-MeOH(NH3) 99-1. as the eluent. Fractions containing the product were evaporated yielding 2.60 g (31%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1)=O.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CCOC(C)=O>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:17][NH:10][C:9]2[CH:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:6][C:5]=2[C:3]([O:2][CH3:1])=[O:4])[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccccc2)cc1NCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.6 %

Procedure:
A suspension of 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (0.70 g, 3 mmol) and 4-formyl N-Cbz-piperidine (0.74 g, 3 mmol) in THF (1.2 mL) was treated with dibutyltin dichloride (46 mg, 0.15 mol) followed by phenylsilane (0.41 mL, 3.3 mmol). The mixture was stirred for 2 days at room temperature. The solvent was then evaporated and the residue was purified by silica gel column chromatography using CH2Cl2:hexanes:EtOAc as eluent to provide 4-[(2-Methoxycarbonyl-5-phenyl-thiophen-3-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (0.6906 g, 50% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:19][CH2:18]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH:17]1([NH:20][C:21](=[O:34])[C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH2:2][C:3]4[CH:16]=[N:15][C:6]5[C:7]6[N:8]([CH:12]=[CH:13][CH:14]=6)[C:9](=[O:11])[NH:10][C:5]=5[CH:4]=4)[CH2:32][CH2:33]3)=[CH:26][CH:27]=2)[CH2:19][CH2:18]1
Reactant: O=C(NC1CC1)c1ccc(N2CCNCC2)cc1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)cc1
Temperature: 95 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (25 mg, 0.116 mmol), N-cyclopropyl-4-(piperazin-1-yl)benzamide (35.6 mg, 0.145 mmol) and (cyanomethyl)trimethylphosphonium iodide (45.2 mg, 0.186 mmol) in Propiononitrile (Volume: 1.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.101 mL, 0.581 mmol) at 23° C. The reaction was stirred at 95° C. for 6 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide N-cyclopropyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0355 g, 0.080 mmol, 69.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.47-0.59 (m, 2 H) 0.59-0.70 (m, 2 H) 2.52-2.59 (m, 4 H) 2.79 (tq, J=7.36, 3.94 Hz, 1 H) 3.19-3.31 (m, 4 H) 3.62 (s, 2 H) 6.70-6.78 (m, 1 H) 6.93 (d, J=9.09 Hz, 2 H) 7.07 (dd, J=3.66, 1.64 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.66-7.68 (m, 1 H) 7.68-7.73 (m, 2 H) 8.14 (d, J=4.29 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.62 (br. s., 1 H). ESI-MS: m/z 443.4 (M+H)+. mp=269.9-271.7° C.