Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([C:13]([C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[B-]C#[N:36].[Na+]>CO>[NH2:36][CH:13]([C:12]1[CH:27]=[CH:28][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)c1ccc(OCc2ccccc2)cc1
Reactant: [B-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(N)c1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
A solution of (R)-tert-butyl 2-(4-(benzyloxy)benzoyl)pyrrolidine-1-carboxylate (247 mg, 0.648 mmol) and dry ammonium acetate (399 mg, 5.18 mmol) in methanol (13.0 mL) was stirred at room temperature for 30 min. To this was added sodium cyanotrihydroborate (81 mg, 1.295 mmol) and the reaction mixture heated to 60° C. for 24 h. An additional portion of sodium cyanotrihydroborate (81 mg, 1.30 mmol) was added and the heating continued at 60° C. for 48 h. The reaction solution was cooled to room temperature, quenched with water and extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (5%→60% ethyl acetate in hexanes). Obtained (R)-tert-butyl 2-(amino(4-(benzyloxy)phenyl)methyl)pyrrolidine-1-carboxylate (100 mg, 0.262 mmol, 100% yield) as a slightly yellow oil that was carried on without further purification. 1H NMR (400 MHz, CDCl3) δ 7.27-7.46 (m, 5H), 6.90-7.15 (m, 4H), 4.97-5.14 (m, 2H), 4.10-4.53 (m, 1H), 3.27-3.64 (m, 1H), 2.55-2.78 (m, 1H), 2.26-2.45 (m, 1H), 1.54-2.11 (m, 4H), 1.45-1.54 (m, 9H); LRMS (ESI) m/e 383.13, 404.11 [(M+H)+, calcd for C23H31N2O3 383.23].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[C:10](=[O:15])[N:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:8]2)=O.[NH2:28][NH2:29]>C(O)C>[CH3:14][C:12]1[CH:13]=[C:5]([C:3]([NH:28][NH2:29])=[O:2])[CH:6]=[C:7]2[C:11]=1[C:10](=[O:15])[N:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[CH2:8]2
Reactant: NN
Reactant: COC(=O)c1cc(C)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Solvent: CCO
Product: Cc1cc(C(=O)NN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid methyl ester (190.0 mg, 0.5 mmol) was mixed with hydrazine (in water) 125.0 mg, 2.50 mmol) in ethanol (0.5 mL) and the reaction was refluxed for five hours. The reaction was concentrated to provide the title compound as an off white solid (200.0 mg, 100%). 1H NMR (300 MHz, CDCl3): δ 7.63 (s, 1H), 7.54 (broad s, 1H), 7.31 (m, 2H), 7.18 (d, 2H), 4.75 (s, 2H), 4.22 (s, 2H), 2.74 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]([NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:25]
Reactant: Cc1cc(Br)cc(C(=O)c2ccccc2)c1N
Reactant: COC(=O)CC(=O)Cl
Product: COC(=O)CC(=O)Nc1c(C)cc(Br)cc1C(=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-5-bromo-3-methyl-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. Light yellow solid. MS (ESI): 392.1 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]([O:21]C)=O)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1[CH:27]=[CH:26]N=C1.OC1C=CC2C3C(=CC=CC=3)C(=O)C=2C=1.[Si](Cl)(C(C)(C)C)(C)C>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:16]2[C:15]3[C:14](=[CH:13][CH:12]=[CH:26][CH:27]=3)[C:19](=[O:21])[C:17]=2[CH:18]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc2c1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: O=C1c2ccccc2-c2ccc(O)cc21
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)C(=O)c1ccccc1-2
Yield: 84 %

Procedure:
The procedure for this reaction was the same as described above for methyl 6-tert-butyldimethylsilyloxy-2-naphthoate. A solution of imidazole (0.5 g, 7.4 mmol) in 2 mL of dry DMF was added to a solution of 2-hydroxy-9-fluorenone (Aldrich, 0.55 g, 2.8 mmol) and tert-butyldimethylsilyl chloride (0.5 g, 3.3 mmol) in 5 ML of dry DMF to give after workup 0.74 g (84%) of a yellow oil: 1H NMR (CDCl3) delta 7.612-6.891 (m, 7H), 0.994 (s, 9H), 0.224 (s, 6H); 13C NMR (CDCl3 delta 193.69, 157.04, 144.87, 137.52, 136.04, 134.73, 134.50, 127.92, 125.59, 124.28, 121.24, 119.56, 16.22, 25.60, 18.18, -4.46. ##STR34##
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:15](OCC)(OCC)OCC>>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:8]2[C:3]3[N:4]([CH:15]=[N:2][N:1]=3)[CH:5]=[CH:6][CH:7]=2)[CH:10]=1
Reactant: CCOC(OCC)OCC
Reactant: NNc1ncccc1-c1cccnc1
Product: c1cncc(-c2cccn3cnnc23)c1
Temperature: 100 °C

Procedure:
A 4.15 g portion of 2-hydrazino-3,3'-bipyridine was dissolved in 30 ml of triethyl orthoformate and heated at 100° C. for 2 hours. The volatiles were removed at reduced pressure and the residue purified by chromatography on hydrous magnesium silicate, eluting with ethyl acetate. The solid was recrystallized from methylene chloride-hexane, giving 2.67 g of the desired product, mp 186°-189° C.
Reaction SMILES: [OH:1][C@:2]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][C:4]([CH2:8][OH:9])([CH3:7])[C:3]1([CH3:11])[CH3:10].[CH3:15]OCOC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:7][C:4]12[C:3]([CH3:11])([CH3:10])[C@@:2]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[O:1][CH2:15][O:9][CH2:8]2
Reactant: COCOC
Reactant: CC1(CO)CC[C@](O)(C(=O)O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC12CC[C@@](C(=O)O)(OCOC1)C2(C)C
Reaction time: 24 h

Procedure:
A mixture of Example 222A (131.6 mg), dimethoxymethane (0.575 mL) and para-toluenesulfonic acid monohydrate (catalytic) in benzene (15 mL) was stirred and heated to reflux with a Dean-Stark trap overnight. An additional 0.5 mL dimethoxymethane was added and heating continued 24 hours. The reaction mixture was evaporated to dryness and flash chromatographed over silica gel eluting with 10% methanol/CH2Cl2 to afford the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 0.88 (s, 3H), 0.94 (s, 3H), 1.15 (s, 3H), 1.88-2.05 (m, 3H), 2.7-2.85 (m, 1H), 3.59 (s, 2H), 5.00 (AB q, J=26.3, 7.9 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23]O)=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C>[N:37]([CH2:23][CH2:22][C:21]#[C:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:3]3[C:2]([OH:1])=[C:7]([C:8]#[N:9])[C:6](=[O:10])[NH:5][C:4]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1)=[N+:38]=[N-:39]
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCO)cc3)csc2[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(O)c2c(-c3ccc(C#CCCN=[N+]=[N-])cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-3-[4-(4-hydroxy-but-1-ynyl)-phenyl]-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (0.23 g, 0.7 mmol) in 5 mL DMF was added triethylamine (0.28 mL, 2 mmol), followed by MsCl (85 μL, 1 mmol). The mixture was stirred at rt for 2 hr, after which NaN3 (0.36 g, 5.6 mmol) was added, and heated to 90° C. overnight. Solvent was removed in vacuo and purified via reverse phase HPLC to afford the titled compound. MS (ESI) m/e 360 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 2.76 (t, J=6.61 Hz, 2H), 3.52 (t, J=6.44 Hz, 2H), 6.67 (s, 1H), 7.29 (d, J=8.48 Hz, 2H), 7.44 (d, J=8.48 Hz, 2H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=1.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:36]2)=[C:28]2[CH:34]=[CH:33][S:32][C:29]2=[N:30][CH:31]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[C:17]1[S:18][CH:19]=[C:20]([C:22]([NH:25][C:26]2[C:27]([N:35]3[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:36]3)=[C:28]3[CH:34]=[CH:33][S:32][C:29]3=[N:30][CH:31]=2)=[O:24])[N:21]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3sccc23)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3sccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A solution of 1-chloro-N,N,2-trimethylpropenylamine (88.5 mg, 0.662 mmol) in DCM (1.0 mL) was added slowly to a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (from step 2 in Example 2, 56.9 mg, 0.236 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 2 h. A solution of tert-butyl [(3S)-1-(5-aminothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (73.3 mg, 0.210 mmol) in DCM (2.0 mL), followed by pyridine (162.6 mg, 2.056 mmol) was then added and the mixture was stirred at room temperature for a further 2 h. The reaction mixture was then concentrated under reduced pressure and the resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a dark oil (118.2 mg, 98%). LCMS calc. for C27H28F2N5O3S2 (M+H)+: m/z=572.2. found 572.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1.O.Cl.[CH3:15][N:16](C)C=O>>[C:15]([C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([CH3:8])=[CH:6][CH:7]=1)#[N:16]
Reactant: COC(=O)c1cc(Br)ccc1C
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1C
Reaction time: 0.5 h

Procedure:
0.5 g of cuprous cyanide was added to 1 g of methyl 4-bromo-o-toluate obtained in Reference example 18 dissolved in 0.7 ml of dimethylformamide and the mixture was refluxed under heating for 6 hours. Then, to the reaction mixture were added 2.6 ml of water, 0.5 ml of conc. hydrochloric acid and 1.75 g of ferric chloride and the mixture was stirred at 60° to 70° C. for 30 minutes. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed from the solution to obtain 0.76 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:27][CH2:26][C:25]4[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: Fc1ccc(CCBr)cc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccc(F)cc3)C2=O)cn1
Yield: 34 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-fluorophenethyl bromide. Yield: 34%. MS M+H calculated 398.16; found 398.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.01 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[NH:10][C:9]=1[CH3:18].[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:18])=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH3:25])[CH3:24])[CH3:20]
Reactant: Cc1[nH]c2ccc(O)cc2c1-c1ccccc1Cl
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3ccccc3Cl)c2c1

Procedure:
The above compound was prepared from 3-(2-chlorophenyl)-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester analogously to Example 10.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=1)[C:23]([OH:25])=O)[CH3:18])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:63][CH:64]([N:66]1[CH:70]=[CH:69][C:68]([NH2:71])=[N:67]1)[CH3:65]>CN(C=O)C>[CH3:12][C:11]([Si:14]([CH3:38])([CH3:37])[O:15][CH2:16][C@@H:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=1)[C:23]([NH:71][C:68]1[CH:69]=[CH:70][N:66]([CH:64]([CH3:65])[CH3:63])[N:67]=1)=[O:25])[CH3:18])([CH3:13])[CH3:10]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: CC(C)n1ccc(N)n1
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: CC(C)n1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.6 %

Procedure:
DIPEA (3.11 mL, 18.03 mmol) was added to a solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (3.00 g, 7.21 mmol), HATU (3.12 g, 8.21 mmol) and 1-(1-methylethyl)-1H-pyrazol-3-amine (1.13 g, 9.01 mmol) in DMF (10 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The DMF was removed in vacuo. The solvent was evaporated and the residue was dissolved in 5% w/v citric acid (50 mL) and ethyl acetate (30 mL) and diethyl ether (30 mL) and the organic layer was further washed with saturated aqueous sodium bicarbonate solution (30 mL) and brine (30 mL). The organic layer was separated, then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:3 ethyl acetate:hexanes, afforded the title compound as a colourless oil (2.40 g, 65%). 1H NMR δ (CDCl3): 0.01 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 1.24 (d, 3H), 1.49 (s, 3H), 1.51 (s, 3H), 3.64 (dd, 1H), 3.78 (dd, 1H), 4.39 (m, 1H), 4.46 (m, 1H), 5.09 (s, 2H), 6.70 (s, 1H), 6.78 (s, 1H), 7.02 (s, 1H), 7.08 (s, 1H), 7.35 (m, 6H), 8.32 (br. s, 1H); m/z 524 (M+H)+, 522 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:35])C(=O)C1.[NH4+].[Cl-].CCOCC>C(#N)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)[C:10]([Cl:35])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCOCC
Product: Cc1c(Cl)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of 100 mg (0.26 mmol) of 2-(1-benzyl-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 80) in 1 mL of acetonitrile were added 25 mg (0.185 mmol) of NCS. After stirring at RT for 2 hrs, the mixture was poured into a mixture of a saturated aqueous solution of NH4Cl and Et2O. The phases were separated and the aqueous one was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with n-heptane/CH2Cl2 1:3 yielded 70 mg (65%) of 2-(1-benzyl-3-chloro-2-methyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, white solid, MS: 420 ((M−H−), 1Cl).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9]>>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][CH2:8][C:7]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCCCNC
Reactant: C=CC(=O)OCC
Product: CCCCN(C)CCC(=O)OCC
Yield: 87.2 %

Procedure:
A stirred mixture of N-methyl-n-butylamine (42.8 g., 0.49 mole) and ethyl acrylate (55 g., 0.54 mole) was heated at 80°-90° C for 20 hours. Excess acrylate was evaporated under reduced pressure, and the residue distilled to give 80.0 g (87%) of the title compound, b.p. 97° C at 12 mm.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9]2)[N:3]=1.[C:14]1([CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][NH2:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[C:12]([C:11]1[C:2]([NH:22][CH2:21][CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:3][C:4]2[C:10]=1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)#[N:13]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: N#Cc1c2cccccc-2nc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c2cccccc-2nc1NCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a solution of 0.38 g (0.002 mol) of 2-chloro-3-cyano-1-azaazulene in 7 ml of dimethylformamide were added 0.43 g (0.0022 mol) of 2,2-diphenylethylamine. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into water with ice to allow precipitate to separate out. The precipitate was filtered and dried to give 0.55 g of title compoind (yield: 78.6%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10])#[N:2].Cl[C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([O:24][CH3:25])[N:18]=[C:17]([O:26][CH3:27])[N:16]=1.[H-].[Na+]>CN(C=O)C>[C:1]([CH:3]([C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([O:24][CH3:25])[N:18]=[C:17]([O:26][CH3:27])[N:16]=1)[C:4]1[CH:11]=[C:8]([C:9]#[N:10])[CH:7]=[C:6]([CH:5]=1)[C:12]#[N:13])#[N:2]
Reactant: N#CCc1cc(C#N)cc(C#N)c1
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C#N)cc(C#N)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
5-Cyanomethyl-isophthalonitrile (0.285 g, 1.70 mmol) and 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (0.360 g, 1.66 mmol) was dissolved in DMF (8.0 mL) and cooled to 0° C. 60% Sodium hydride (0.136 g, 3.40 mmol) was added portionwise and the reaction was stirred at 0° C. for 2 h, then rt overnight. The reaction was quenched with saturated ammonium chloride solution and pH was adjusted to ˜6.0 with 1N HCl. Mixture was extracted with ethyl acetate and organic layer was dried (MgSO4) and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexane) to give a white solid (0.2457 g, 43%). 1H NMR (300 MHz, CDCl3): δ 7.90 (s, 3H), 5.46 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.05-2.9 (m, 1H), 1.16 (d, J=6.9 Hz, 3H), 1.15 (d, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12]3\[O:13][C:14]([CH3:24])([CH3:23])[C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:16]\3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[I-:25].[Na+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[CH3:23][C:14]1([CH3:24])[O:13]/[C:12](=[C:6]2/[C:7](=[O:11])[NH:8][C:9]3[C:5]/2=[CH:4][CH:3]=[C:2]([I:25])[CH:10]=3)/[CH:16]=[C:15]1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: [I-]
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(Br)ccc32)C=C1N1CCOCC1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(I)ccc32)C=C1N1CCOCC1
Temperature: 110 °C

Procedure:
To a heavy-wall pressure tube were added (3E)-6-bromo-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-1,3-dihydro-2H-indol-2-one (1.6 g, 4.09 mmol), copper(I)iodide (39 mg, 0.20 mmol), sodium iodide (1.23 g, 8.18 mmol), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (58 mg, 0.41 mmol), and 20 mL of anhydrous 1,4-dioxane. The mixture was purged with nitrogen, sealed and heated in 110° C. bath for 3 days. The mixture was poured into 200 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude product, (3E)-3-(5,5-dimethyl-4-morpholin-4-ylfuran-2(5H)-ylidene)-6-iodo-1,3-dihydro-2H-indol-2-one, as a brown solid. Yield: 2.1 g. This crude material was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:19])[N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[N:3]=1.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30].O>CN1C(=O)CCC1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[C:10]2[C:5](=[C:4]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:3]=[C:2]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:19]
Reactant: NC(CO)CO
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1ccccc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NC(CO)CO)cc2n1-c1ccccc1Cl
Yield: 23.2 %

Procedure:
7-Bromo-1,5-bis(2-chlorophenyl)[1,6]naphthyridin-2(1H)-one (38 mg, 0.085 mmol) was dissolved in NMP (2 ml) and serinol (2-amino-1,3-propanediol) (35 mg, 0.384 mmol) added, and the solution heated in a Smith creator microwave at 220° for 0.5 h. After cooling, the solution was added to water (12 ml) and extracted with dichloromethane (10 ml). The mixture was passed through a hydrophobic frit and evaporated in vacuo. The residue was purified by SPE (SiO2, 10 g) eluting with dichloromethane-methanol (98:2) to afford the title compound as a gum (9 mg, 23%).
Reaction SMILES: [CH3:1][N:2]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[N:3]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Cl.[CH:35]1([NH2:38])[CH2:37][CH2:36]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH:35]1([NH:38][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([CH2:14][N:3]([C:4]([O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:5])[N:2]([CH3:1])[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[CH:16][CH:17]=2)[CH2:37][CH2:36]1
Reactant: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)Cl)cc1)C(=O)OCc1ccccc1
Reactant: NC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)NC2CC2)cc1)C(=O)OCc1ccccc1

Procedure:
16.5 g. of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)methyl]-benzoyl chloride were added to 100 ml. of absolute benzene and treated with 3.1 g. of cyclopropylamine hydrochloride. 7.5 g. of triethylamine and 50 ml. of benzene were then dropped into the reaction mixture at 20°-30° with stirring. The reaction mixture was worked up as in Example 3, yielding 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoic acid cyclopropylamide, the carbobenzoxy groups of which were then removed by treatment with hydrogen bromide/glacial acetic acid. The product, 4-[(2-methyl-hydrazino)-methyl]-benzoic acid cyclopropylamide hydrobromide, melted at 180°-182°.