Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31].C(N(C(C)C)C(C)C)C>C(O)CC>[OH:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH:31][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1
Reactant: NCc1cccc(O)c1
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Oc1cccc(CNc2ncnc3c2ncn3C2CCCO2)c1
Yield: 85 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)-purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) of 3-hydroxybenzylamine, and 5 ml of N-ethyldiisopropylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 85%, white solid. TLC (EtOAc:hexane (1:1 (v:v)): single spot; HPLC: purity>98%. 1H NMR (400 MHZ, DMSO): 2.20sep (1H, J=6.8 Hz); 2.22sep (1H, J=6.8 Hz); 2.44m (2H); 3.91 q (1H, J=7.3 Hz); 4.14q (1H, J=7.3 Hz); 4.63bs (2H); 6.26m (1H); 6.59dd (1H, Ja=7.8 Hz, Jb=2.2 Hz); 6.73s (1H); 6.75d (1H, J=7.8 Hz); 7.07t (1H, J=7.8 Hz); 8.20s (1H); 8.26bs (1H); 8.27s (1H); 9.23bs (1H). MS (ES): [M+H]+=312 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].I[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: Nc1ccccc1Cl
Reactant: CC(=O)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CNc1ccccc1Cl
Temperature: 100 °C
Yield: 69.7 %

Procedure:
A mixture of 2-chloroaniline (13.2 ml, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18.1 g, 0.13 mol) in DMF (200 ml) was heated under nitrogen at 100° C. overnight. After cooling to rt, water was added and the mixture extracted with ether (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (Heptane:EtOAc 80:20) afforded 16.0 g (70%) of the title compound as a brown liquid.
Reaction SMILES: S(=O)(=O)(O)O.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([CH:15]([OH:17])[CH3:16])=[N:7]1>O.C(OCC)C>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15](=[O:17])[CH3:16])=[N:7]1
Reactant: CC(O)c1noc2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)c1noc2ccccc12
Reaction time: 1 h

Procedure:
A mixture of 1.1 g of sodium bichromate dihydrate and 0.8 ml of sulfuric acid in 5 ml of water is slowly added dropwise to 1.6 g of 1-(1,2-benzisoxazol-3-yl)ethanol in 5 ml of diethyl ether. This mixture is stirred for 1 hour at room temperatur and then, with ice cooling, 50 ml of water are added and extraction wth diethyl ether is carried out three times. The combined ethereal extracts are washed once with a saturated solution of sodium bicarbonate, once with water and finally once with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by chromatography over silica gel with ethyl acetate/hexane (1:3), giving 1-(1,2-benzisoxazol-3-yl)ethanone having a melting point of 30°-32° C.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br.[Br:10][C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[C:13]([CH2:18][C:19]#[N:20])[C:12]=1[O:21][CH3:22].Cl>CN(C)C=O.O>[C:19]([C:18]1([C:13]2[CH:14]=[C:15]([Br:17])[CH:16]=[C:11]([Br:10])[C:12]=2[O:21][CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:20]
Reactant: COc1c(Br)cc(Br)cc1CC#N
Reactant: BrCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(Br)cc(Br)cc1C1(C#N)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (7 g) in dry dimethylformamide (200 ml) was added a solution of 1,5-dibromopentane (20 ml) and the product of stage (d) in dimethylformamide (40 ml), keeping the temperature at 20°-30° C. The mixture was stirred for 30 minutes, water was added cautiously, and was then poured into ice water. Hydrochloric acid was added and the mixture was extracted with dichloromethane, washed with water and brine, dried over magnesium sulphate and filtered, and the solvent was removed to give a pale brown oil which slowly crystallised. Recrystallisation from ethanol gave the title product as yellow crystalls, mp 100°-102° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:8][O:9][CH2:10][CH2:11][OH:12])=[CH:3][CH:2]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:8][O:9][CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)=[CH:3][CH:2]=1
Reactant: OCCON=Cc1ccncc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccncc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 41.7 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 0.88 g of 2-(4-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 6), 2.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 1.32 ml of tributylphosphine and 1.23 g of 1,1'-(azodicarbonyl)dipiperazine, 1.10 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:19][C:20]([CH3:22])=[CH2:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:23])[CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:20](=[CH2:21])[CH2:19][N:8]([C:6]1[CH:5]=[C:4]([CH3:23])[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)[N:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 85 °C
Yield: 59.9 %

Procedure:
To a degassed solution of (6-chloro-4-methyl-pyridin-2-yl)-(2-methyl-allyl)-(4-trifluoromethyl-phenyl)-amine (340 mg, 1.0 mmol), 4-trifluoromethylbenzeneboronic acid (230 mg, 1.2 mmol), 2N Na2CO3 (1.5 mL) in DME (10 mL) was added tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) under argon. The mixture was heated to 85° C. for 4 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (5-20% methylene chloride in methylene chloride) to give the product as a white solid (270 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.91 Hz, 2H), 7.69 (d, J=8.29 Hz, 2H), 7.59 (d, J=8.67 Hz, 2H), 7.39 (d, J=8.67 Hz, 2H), 7.11 (s, 1H), 6.66 (s, 1H), 4.86 (s, 2H), 4.70 (s, 2H), 2.30 (s, 3H), 1.81 (s, 3H). MS m/e 451.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>>[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:43])=[O:42])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1

Procedure:
4-(Methylsulfonyl)-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)-phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 4-methylsulfonylbenzenesulfonylchloride (61 mg, 0.455 mmol) according to general method 3 to give 70 mg of a purple solid. MS (posES-FIA) m/z=Found: 551.2; Calcd: 551.10.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([F:26])=[C:19]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:20]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:26][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:6]3[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]3[N:1]=[CH:11][CH:12]=2)=[CH:20][C:19]=1[N:21]([CH3:25])[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Reactant: N#Cc1cn[nH]c1N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)cnn23)ccc1F
Yield: 80.8 %

Procedure:
A mixture of 0.041 g (0.38 mmol) of 5-amino-1H-pyrazole-4-carbonitrile and 0.1 g (0.38 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. Dichloromethane (15 mL) and a saturated sodium bicarbonate solution (10 mL) were added to the resulting residue. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 95 mg of N-{2-fluoro-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 81%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].C(O[C:12](=[O:14])[CH3:13])(=O)C.[OH-].[Na+]>CCOCC.O>[C:12]([N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])(=[O:14])[CH3:13]
Reactant: CNCCN(C)C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(=O)N(C)CCN(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
N-Acetyl-N,N',N'-trimethylethylenediamine intermediate was prepared in the following manner. N,N,N'-Trimethylethylenediamine (24.5 g, 0.24 mol) was added to acetic anhydride (38 mL, 0.40 mol) over 1.5 hours with cooling in an ice-water bath. After stirring another 22 hours at ambient temperature, the reaction mixture was diluted with 50 mL of ether and 25 mL of water, and then cooled in an ice-water bath. A solution of 25 percent aqueous NaOH was added until the pH was approximately 10 and the phases were separated. The aqueous phase was extracted two more times with ether and the combined organic phase was concentrated on the rotary evaporator (50°,>100 mm Hg). Yield=2.4 g. The aqueous phase was saturated with NaCl and extracted again with methylene chloride (3×25 mL). After evaporation, it gave a total of 33.4 g of yellow liquid. Distillation through a 1×8 cm Vigreux column afforded 23.53 g of colorless liquid, bp 90°-1°/7 mm Hg (68 percent yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1([CH3:20])[O:13][C:12]2=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:11]2[CH2:10]1)(=O)=O.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C.[I-].[K+]>CN(C=O)C>[CH3:20][C:9]1([CH2:8][CH2:7][CH2:6][N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)[O:13][C:12]2=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:11]2[CH2:10]1
Reactant: CC1(CCCOS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CCCC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl methane-sulfonate (2 g, 6.6 mmol), tert-butyl piperazine-1-carboxylate (1.4 g, 7.5 mmol), triethylamine (1.3 g, 12.85 mmol), potassium iodide (1.8 g, 10.8 mmol) and DMF (15 ml) was stirred at 60° C. overnight. The reaction mixture was allowed to return to room temperature and then added water, and the resulting solution was extracted with ethyl acetate three times. The organic phases were combined, washed with water twice and then with a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to afford tert-butyl 4-[3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-yl)propyl]piperazine-1-carboxylate (1.9 g, yield 73%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Clc1nccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(-c2nccc3ccccc23)c(F)c1
Temperature: 25 °C

Procedure:
2,4-difluorophenylboronic acid (Aldrich Chemical Co., 13.8 g, 87.4 mmol), 1-chloroisoquinoline (Adrich Chemical Co., 13 g, 79.4 mmol), tetrakistriphenylphosphine palladium(0) (Aldrich, 3.00 g, 2.59 mmol), potassium carbonate (EM Science, 24.2 g, 175 mmol), water (300 mL), and dimethoxyethane (Aldrich, 300 mL) were allowed to stir at reflux for 20 h under N2, after which time the mixture was cooled to room temperature and the organic and aqueous layers were separated. The aqueous layer was extracted with 3×150 mL of diethyl ether, and the combined organic fractions were dried with sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude material was chromatographed on a silica gel column, first by eluting the catalyst byproduct with 4:1 hexanes/CH2Cl2, and finally the product was eluted with CH2Cl2/MeOH (9.5:0.5, product Rf=0.7). The pure product fractions were collected and dried in vacuo, to afford 17.7 g (92% isolated yield) of a light yellow solid, >95% pure NMR spectroscopy. 1H NMR (CDCl3, 296 K, 300 MHz): δ 8.61 (1H, d, J=5.7 Hz), 7.89 (1H, d, J=8.2 Hz), 7.67–7.85 (3H, m), 7.52–7.63 (2H, m), 6.95–7.12 (2H, m) ppm. 19F NMR (CDCl3, 296K, 282 MHz) δ −109.01 (1F, brs), −109.87 (1F, d, JF-F=8.5 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)#[N:11].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:43]1([C@H:47]([NH:54][CH3:55])[CH2:48][N:49]2[CH2:52][CH:51]([OH:53])[CH2:50]2)[CH2:46][CH2:45][CH2:44]1>C(Cl)Cl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([N:54]([C@@H:47]([CH:43]2[CH2:46][CH2:45][CH2:44]2)[CH2:48][N:49]2[CH2:50][CH:51]([OH:53])[CH2:52]2)[CH3:55])=[O:18])=[CH:19][CH:20]=1)#[N:11]
Reactant: CN[C@H](CN1CC(O)C1)C1CCC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ccc(C#N)cc1)[C@H](CN1CC(O)C1)C1CCC1
Reaction time: 0.08 h
Yield: 64.9 %

Procedure:
DIPEA (2.504 mL, 14.38 mmol) was added to a stirred suspension of 4-cyanobenzoic acid (0.670 g, 4.55 mmol) and TBTU (1.462 g, 4.55 mmol) in DCM (10 mL) at rt. The suspension was stirred for 5 min before it was cooled on an ice-bath. A solution of (S)-1-(2-cyclobutyl-2-(methylamino)ethyl)azetidin-3-ol (Compound Z2.1) (0.960 g, 4.79 mmol) in DCM (10 mL) was added over 5 min. The ice-bath was removed after 10 min and the reaction was stirred at rt for 3 h. The reaction mixture was diluted with DCM (20 mL), washed with NaHCO3 (8% aq., 35 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC. The selected fractions were concentrated and NaHCO3 (saturated, 40 mL) was added. The water layer was extracted with DCM (3×75 mL) and the combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.925 g, 62%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6) δ 1.32-1.62, 1.65-1.97, 1.97-2.08, 2.17-2.28, 2.32-2.60, 2.62-2.74, 3.16-3.27, 3.39-3.45, 3.46-3.52, 4.07-4.18, 4.40-4.52, 5.19-5.24, 7.42-7.46, 7.57-7.62, 7.87-7.95.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:27]([C:29]1[C:30](=[C:45]([C:48]#[N:49])[C:46]#[N:47])[O:31][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:35]([F:38])([F:37])[F:36])[C:33]=1[CH3:34])#[N:28]>C(O)C.O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:34][C:33]3[C:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:35]([F:38])([F:36])[F:37])[O:31][C:30](=[C:45]([C:48]#[N:49])[C:46]#[N:47])[C:29]=3[C:27]#[N:28])=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)s2)c(OC)c1
Temperature: 70 °C
Yield: 92.7 %

Procedure:
In 8 ml of ethanol and 2.5 ml of tetrahydrofuran were dissolved 226 mg (0.61 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde and 210 mg (0.62 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 70° C. for 4 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 378 mg of a dark brown powdered crystal (yield: 92.9%; mp: 203-204° C.)
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[N:6][C:5]([SH:8])=[N:4]1.[CH2:9](Br)[C:10]#[CH:11]>CO>[CH2:11]([S:8][C:5]1[N:6]=[CH:7][NH:3][N:4]=1)[C:10]#[CH:9]
Reactant: Sc1nc[nH]n1
Reactant: C#CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#CCSc1nc[nH]n1
Temperature: 25 °C

Procedure:
To a solution of 21.8 g of potassium hydroxide in 400 ml of methanol under nitrogen was added 33.37 g of 1,2,4-triazole-3-thiol. The resulting mixture was stirred at ambient temperature for ~1 hour. To this mixture was added 33.4 ml of propargyl bromide dropwise while keeping the reaction temperature below 30° C. After the addition, the resulting mixture was stirred at ambient temperature for ~4 hours and was then concentrated under reduced pressure. The residue was triturated in 300 ml of water. The precipitate was collected by filtration, washed with water and then hexanes, air dried and then dried in oven to give 24.6 g of the title product as a solid, m.p. 102°-104° C. NMR (DMSO-d6): 3.14 (t, 1H); 3.92 (d, 2H); 8.48 (s, 1H); 14.2 (bs, 1H).
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:17][C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:24]=[C:25]([NH:26][C:14]([C:1]3[C:13]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:15])[CH:27]=[CH:28][CH:29]=2)[CH:22]=1
Reactant: Cc1cn(-c2cccc(N)c2)cn1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1cn(-c2cccc(NC(=O)c3cccc4c3Cc3ccccc3-4)c2)cn1
Reaction time: 24 h
Yield: 29.2 %

Procedure:
To a suspension of 9H-fluorene-1-carboxylic acid (79 mg) and 3-(4-methylimidazol-1-yl)aniline (65 mg) in dichloromethane (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (101 mg) and 4-dimethylaminopyridine (23 mg), and the mire was stirred for 24 hours. The mix e was diluted with dichloromethane, washed with water and brine. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with methanol, and the insoluble material was collected by filtration and dried to give N-[3-(4-methylimidazol-1-yl)-phenyl]-9H-fluorene-1-carboxamide (40 mg, 29.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].[H-].[Na+].[C:27](Cl)(=[O:29])[CH3:28]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[O:29]=[C:27]1[N:14]2[CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]3[C:15]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:28]1
Reactant: CCOC(=O)Nc1cccc2c1NC1CCN(C(=O)OCC)CC21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC2C(C1)c1cccc3c1N2C(=O)CN3C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
To a solution of ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (2.2 g, 6.6 mmol) in DMF (20 mL) at 0° C. was added NaH (660 mg, 16.5 mmol), DMAP (878 mg, 7.2 mmol), acetyl chloride (0.6 mL, 7.2 mmol) and stirred at rt for 16 hours. The solution was diluted with water (30 mL), and extracted with EtOAc (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford diethyl 1-oxo-6b,9,10,10a-tetrahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-3,8(2H,7H)-dicarboxylate (1.1 g, 57%) as a clear oil. MS [M+H]+374. 1H NMR (CDCl3, 300 MHz): δ 6.75 (t, 1H, J=7.7 Hz), 6.59 (m, 1H), 6.45 (m, 1H), 4.05 (m, 1H), 3.60-4.00 (m, 7H), 3.40 (m, 1H), 3.00 (m, 3H), 1.92 (m, 2H), 0.91 (m, 1H), 0.85 (m, 6H) ppm.