Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[C:44]([Cl:49])[CH:43]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:49][C:44]1[CH:43]=[C:42]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:41])[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:28]=3)[CH2:21]2)[CH:47]=[CH:46][C:45]=1[Cl:48]
Reactant: CS(=O)(=O)OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[[3,5-bis(trifluoromethyl)phenyl]acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: COC1C=C(C2ON=C(CSC3NC4C=CC=CC=4N=3)N=2)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:31][C:32]1[S:36][CH:35]=[C:34]([C:37]2[O:41][N:40]=[C:39]([CH2:42]ON3C4C=CC=CC=4N=N3)[N:38]=2)[CH:33]=1.[CH2:53]([N:55]1[C:59]([C:60]2[O:61][CH:62]=[CH:63][CH:64]=2)=[N:58][NH:57][C:56]1=[S:65])[CH3:54]>CCCCCCC.CCOC(C)=O>[Cl:31][C:32]1[S:36][CH:35]=[C:34]([C:37]2[O:41][N:40]=[C:39]([CH2:42][S:65][C:56]3[N:55]([CH2:53][CH3:54])[C:59]([C:60]4[O:61][CH:62]=[CH:63][CH:64]=4)=[N:58][N:57]=3)[N:38]=2)[CH:33]=1
Reactant: Clc1cc(-c2nc(COn3nnc4ccccc43)no2)cs1
Reactant: CCn1c(-c2ccco2)n[nH]c1=S
Agent: COc1cccc(-c2nc(CSc3nc4ccccc4[nH]3)no2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCn1c(SCc2noc(-c3csc(Cl)c3)n2)nnc1-c1ccco1

Procedure:
The title compound was prepared according to method for 2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole, with the exception of using molar equivalent cesium carbonate instead of potassium carbonate as the base, from 1-[5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriazole (32.3 mg, 0.097 mmol) and 4-ethyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione (23 mg) by using 50% EtOAc in n-heptane as chromatography eluent to yield 21 mg. 1H NMR (CDCl3) d (ppm): 7.95 (d, 1H), 7.57 (dd, 1H), 7.44 (d, 1H), 7.07 (dd, 1H), 6.56 (dd, 1H), 4.56 (s, 2H), 4.22 (q, 2H), 1.35 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(O[C:26](OC2N=CC=CC=2)=[S:27])N=CC=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:18]=[C:26]=[S:27])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1ccc(N)c2c1N(C(=O)OC(C)(C)C)CC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N=C=S)c2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h
Yield: 93.6 %

Procedure:
1-t-Butoxycarbonyl-4-amino-2,3-dihydro-7-methylindole (1.625 g, 6.55 mmol) is dissolved in methylene chloride (15 mL). To this solution is added 4-dimethylaminopyridine (0.160 g, 1.31 mmol) and di-2-pyridyl thionocarbonate (1.52 g, 6.55 mmol). The volume of solvent is brought to 30 mL, and the solution is allowed to stir for one hour. The solution is diluted to 150 mL with chloroform and washed first with four 75-mL portions of aqueous citric acid solution followed by three 100-mL portions of aqueous potassium carbonate. The organic layer is dried over anhydrous potassium carbonate, filtered and the solvent is removed by rotary evaporation to yield an orange, oily solid. The crude product is purified by silica gel flash column chromatography using 4% ethyl acetate/hexanes to afford 1.78 g of N-t-butoxycarbonyl-2,3-dihydro-4-isothiocyanato-7-methylindole as a white solid (94% yield).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27](O)=[O:28].[NH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:32]1([CH2:31][NH:30][C:27]([C:3]2[C:4]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:17]=[CH:16][N:15]=[C:14]5[CH:18]=[C:19]([C:21]6[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=6)[S:20][C:13]=45)=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])=[O:28])[CH2:34][CH2:33]1
Reactant: NCC1CC1
Reactant: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NCC1CC1
Yield: 81.2 %

Procedure:
This material was prepared from the reaction of 2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}benzo[b]thiophene-3-carboxylic acid 117b (70 mg, 0.166 mmole), (aminomethyl)cyclopropane (43 μL, 0.50 mmole) and diisopropylethylamine (58 μL, 0.33 mmole), and HBTU (94 mg, 0.25 mmole) in a manner similar to that previously described for example 117 to afford a pale yellow solid (64 mg, 53%). 1H NMR (DMSO-d6, 300 MHz) δ8.61 (1H, d, J=5.46 Hz), 8.49 (1H, t, J=5.65 Hz), 8.07 (1H, s), 7.99 (1H, d, J=2.26 Hz), 7.85 (1H, d, J=8.67 Hz), 7.63 (1H, s), 7.37 (1H, s), 7.36 (1H, dd, J=2.4, 8.67 Hz), 6.81 (1H, d, J=5.65 Hz), 4.01 (3H, s), 3.20 (2H, t, J=6.31 Hz), 2.62 (3H, s), 1.08 (1H, m), 0.47 (2H, m), 0.27 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][CH:12]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[C:13]#[CH:14]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:14]#[C:13][CH:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH3:11])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1I
Reactant: C#CC(C)c1cc(OC)c(OC)c(OC)c1
Product: COc1cc(C(C)C#Cc2c(C)nc(N)nc2N)cc(OC)c1OC
Yield: 85.9 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 5-(But-3-yn-2-yl)-1,2,3-trimethoxybenzene (440 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)but-1-ynyl)-6-methylpyrimidine as a white powder (294 mg, 86%): Rf=0.29 (9:1, CHCl3:MeOH); mp=191-193° C.; 1H NMR (DMSO-d6) δ 6.76 (s, 2H), 6.19 (s, 2H), 4.02 (q, J) 7.1 Hz, 1H), 3.77 (s, 6H), 3.63 (s, 3H), 2.21 (s, 3H), 1.51 (d, J) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 167.0, 164.1, 161.0, 152.8, 139.4, 136.0, 104.0, 100.8, 88.6, 76.4, 60.0, 55.8, 32.5, 24.6, 22.5; Anal. (C18H22N4O3) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([NH2:16])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=2)=[C:4]([C:3]([O:2][CH3:1])=[O:17])[NH:16][C:25]1=[O:26]
Reactant: COC(=O)C(N)C(=O)Cc1ccc(F)c(F)c1
Reactant: O=C=NCCCCCBr
Solvent: O
Product: COC(=O)c1[nH]c(=O)n(CCCCCBr)c1Cc1ccc(F)c(F)c1
Yield: 55 %

Procedure:
To 2-amino-4-(3,4-difluorophenyl)-3-oxobutyric acid methyl ester (0.100 g, 0.344 mmol) in 2 mL water was added 1-bromo-5-isocyanatopentane (0.3 mL), and the reaction mixture refluxed for 3 hours. The reaction mixture was concentrated and partitioned between EtOAc (30 mL) and 1N HCl (10 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (10 mL), dried over sodium sulfate, filtered and concentrated to give 0.080 g (55%) of the product as a syrup; 1H-NMR (CDCl3) δ1.36-1.81 (m, 6 H), 3.34 (t, J=6.6 Hz, 2 H), 3.32-3.37 (m, 2 H), 3.86 (s, 3 H), 4.21 (s, 2 H), 6.91-7.16 (m, 3 H), 9.53 (s, 1 H).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH:26](OC)OC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.CN(C=O)C>C1C=CC=CC=1>[C:1]([N:9]1[C@@H:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:17][CH:24]1[O:25][CH3:26])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1OC(OC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Temperature: 103 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
[R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (1.16 mmol) was suspended in benzene (10 ml), and trimethoxymethane (3.44 mmol) and PPTS (72 mg) were added. Heating to reflux (103° C.) did not dissolve the starting compound. 2 ml of DMF were then added so that most of the starting compound dissolved, although the solution remained somewhat turbid. The flask was equipped with a Soxhlet extractor. The thimble of the extractor was filled with 4 Å mol. sieves. After 1 hour, and approximately 3 to 4 cycles in the Soxhlet extractor, TLC showed consumption of the starting material, and a new major spot of the title product. It was diluted with EtOAc, washed with NaHCO3 and H2O, dried and the solvent removed. NMR showed the presence of the title product and a small impurity. The product was purified on HPLC (hexane:ethyl acetate, 3:1) to give 358 mg (87%) of the title product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14](OCC)=[O:15])=[CH:5][CH:4]=1)#[N:2].CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[CH:14]([C:10]1[N:11]=[CH:12][O:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:15]
Reactant: CCOC(=O)c1ncoc1-c1ccc(C#N)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ocnc2C=O)cc1
Yield: 85.7 %

Procedure:
To a solution of ethyl 5-(4-cyanophenyl)oxazole-4-carboxylate (500 mg, 2.06 mmol, 1.00 equiv) in anhydrous THF (10 mL) maintained under nitrogen at −78° C. was added dropwise a 25% solution of DIBAL (2.5 mL) in toluene with stirring. The resulting solution was stirred at −40° C. for 3 h and then quenched by the addition of 10 mL of water. The mixture was extracted with 2×10 mL of ethyl acetate. The combined organic layers was washed with 1×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to yield 350 mg (86%) of 4-(4-formyloxazol-5-yl)benzonitrile as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 10.16 (s, 1H), 8.42 (d, J=8.4 Hz, 2H), 8.04 (s, 1H), 7.83 (d, J=8.4 Hz, 2H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15]>O1CCCC1.[Cl-].[Na+].O>[CH3:1][N:2]1[C:6]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:4]=[N:3]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1ccnn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Temperature: -78 °C
Yield: 65.7 %

Procedure:
A solution of 1-methyl-1H-[1,2,3]triazole (350 mg) in dry tetrahydrofuran (5.0 ml) was added dropwise under nitrogen to a stirred, cooled (-78° C.) solution of n-butyl lithium (2.81 ml of 1.6M solution in hexanes) in dry tetrahydrofuran (10 ml). After 1 hour tributylchlorostannane (1.46 g) was added. The reaction was maintained at -78° C. for 30 min. and then allowed to warm to room temperature over 2 hours. The reaction mixture was diluted with brine (10 ml) and extracted into ethyl acetate (50 ml). The organic layer was separated, washed with brine (50 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by flash column chromatography (20% ethyl acetate/n-hexane), to give 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole as a yellow oil (1.03 g). 1H NMR (360 MHz,CDCl3) δ 0.87 (9H, m), 1.15 (6H, m), 1.28 (6H, m), 1.36 (6H, m), 4.02 (3H, s), 7.60 (1H, s); MS m/z CI+ 372 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C@@H:8]([C@@:10]1([CH3:31])[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH2:13][N:12]([C:24](=[O:30])[CH2:25][S:26][C:27](=[O:29])[CH3:28])[CH2:11]1)[CH3:9].[CH:32]1([CH2:35]Br)[CH2:34][CH2:33]1>CN(C=O)C.O>[OH:7][C@@H:8]([C@@:10]1([CH3:31])[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:35][CH:32]3[CH2:34][CH2:33]3)[CH:16]=2)[CH2:13][N:12]([C:24](=[O:30])[CH2:25][S:26][C:27](=[O:29])[CH3:28])[CH2:11]1)[CH3:9]
Reactant: COc1ccc([C@@H]2CN(C(=O)CSC(C)=O)C[C@@]2(C)[C@@H](C)O)cc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([C@@H]2CN(C(=O)CSC(C)=O)C[C@@]2(C)[C@@H](C)O)cc1OCC1CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
To a flask containing anhydrous K2CO3 (52 mg, 0.37 mmol, 4.0 eq) under a nitrogen atmosphere was added a solution of Example 118 (34 mg, 0.093 mmol, 1 eq) in anhydrous DMF (1 mL). Cyclopropylmethyl bromide (40 μL, 0.37 mmol, 4.0 eq) was added via syringe to the mixture. The slurry was stirred at 65° C. overnight. The reaction was cooled to room temperature, then diluted with water (50 mL). The aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic layers were washed with brine (50 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The resulting oil was purified by preparative TLC plate (100% EtOAc), yielding a clear, colorless oil (13.9 mg, 36%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)C(C)C)(C)C.[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:36]([N:23]1[CH2:24][CH2:25][CH2:26][C@@H:21]([CH2:20][N:17]2[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)=[O:13])[CH2:15][CH2:16]2)[CH2:22]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)-1-[(3R)-piperidin-3-ylmethyl]piperazine-4-carboxamide dihydrochloride (800 mg) in dichloromethane (25 mL) was added N,N-di-iso-propylethylamine (0.94 mL) under argon. The mixture was stirred at room temperature for 5 minutes before benzaldehyde (0.22 mL) and sodium triacetoxyborohydride (573 mg) were added. The reaction mixture was stirred at room temperature under argon for 4 hours. The reaction was quenched with water and then partitioned between dichloromethane and water. The organic extract was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in dichloromethane to give the title compound as a white solid (550 mg, 66%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH3:22][CH:23]([CH3:26])[C:24]#[CH:25]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:25]#[C:24][CH:23]([CH3:26])[CH3:22]
Reactant: C#CC(C)C
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)C#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 70 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (447 mg, the compound of Example A1) in triethylamine (10 ml) at room temperature was added 3-methylbut-1-yne (0.5 ml), cuprous iodide (15 mg) and bis(triphenylphosphine)palladium(II) chloride (30 mg). The reaction mixture was heated at 70° C. for two hours. The reaction mixture was partitioned between ether (100 ml) and water (100 ml). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with dichloromethane: hexane (1:1) to provide the title compound as a pale yellow solid m.p. 210-2° C.
Reaction SMILES: [NH:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3.[CH3:20][C:21](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:20]([N:1]1[C:7]2=[C:8]3[C:13](=[N:14][C:15]4=[CH:16][CH:17]=[CH:18][C:5](=[C:6]24)[O:4][CH2:3][C:2]1=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH3:21]
Reactant: O=C1COc2cccc3nc4c(c(c23)N1)CCCC4
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.33 h
Yield: 81.6 %

Procedure:
To a suspension of 1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (5.0 g) in dry tetrahydrofuran (110 ml) was added potassium tert-butoxide (2.65 g). The mixture was stirred for 20 mins, bromoethane (5.88 ml) was added, and the reaction mixture was refluxed for 6.5 hrs. The reaction mixture was concentrated, diluted with saturated potassium carbonate solution, and extracted with ethyl acetate. The organic extractions were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was adhered to silica and flash chromatographed (20% ethyl acetate/hexane) to yield 4.53 g (82%) of 1-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1.NC1C=CC(N2C=CC=CC2=O)=CC=1F>>[NH2:21][C:20]1[CH:22]=[CH:23][C:17]([N:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]2=[O:15])=[CH:18][C:19]=1[F:24]
Reactant: Nc1ccc(Br)cc1F
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: Nc1ccc(-n2ccccc2=O)cc1F
Product: Nc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1F

Procedure:
1-(4-Amino-3-fluoro-phenyl)-4-benzyloxy-1H-pyridin-2-one was prepared from 4-benzyloxy-1H-pyridin-2-one and 4-bromo-2-fluoroaniline in analogy to the procedure described for the preparation of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one described in C. F. Bigge et al., patent application WO 2003045912. MS: 311 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:21]#[C:22][NH2:23].[Na].C>C1COCC1>[C:1]([NH:23][C:22]#[N:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: N#CN
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)NC#N
Reaction time: 63 h
Yield: 92.4 %

Procedure:
Stearoyl chloride (3.03 g, 0.010 mol) in 50 ml of freshly distilled dry THF was added drop-wise to a suspension of sodium cyanamide (1.92 g, 0.030 mol) in 100 ml of freshly distilled dry THF with vigorous stirring. The reaction was allowed to proceed at 25° C. for 63 hours. The solids which formed were collected by filtration and the solid cake was suspended in 200 ml of distilled water. The resulting soapy suspension (pH 10.5) was acidified to pH 1.5 with 10% HCl, filtered, and air-dried to give 2.85 g (92.4% yield) of crude 7. This was dissolved in THF and the solution decolorized with activated charcoal. The filtrate was concentrated until the solution became turbid. Addition of petroleum ether gave 2.29 g (crop 1) of white waxy 7. The filtrate was concentrated and petroleum ether added to give 0.28 g (crop 2) of additional product giving a total yield of 83.3%, mp 74°-75 ° C. TLC: Rf =0.69 in EtOAc/petroleum ether/AcOH (50:100:1), detected by UV quenching (weak) and no color reaction with ferricyanide spray reagent; IR (Nujol, cm-1) 3210 (NH), 2250 (C≡N), 1735 (C=O); NMR (Silanor C, δ from TMS) 2.3-2.6 (t, --CH2 --CH2 --C=O), 1.0-1.8 (fused s, (CH2)14), 0.8-0.9 (t, CH3 --CH2 --); Anal. Calcd for C19H36N2O: C, 73.97; H, 11.76; N, 9.08. Found: C, 73.88; H, 11.50; N, 9.09.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[Cu][C:22]#[N:23]>CN(C=O)C>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[C:22]#[N:23]
Reactant: O=c1[nH]nc(Cc2ccc(F)c(Br)c2)c2c1CCCC2
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F
Temperature: 160 °C

Procedure:
To a solution of 4-(3-bromo-4-fluoro-benzyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one (9) (9.53 g, 28.2 mmol), in dry DMF (95 ml) was added copper (I) cyanide (3.5 g, 42.3 mmol) in one portion. The mixture was heated to 160° C. for 18 hours. The reaction was then cooled and filtered through celite and washed though with methanol (30 ml). The filtrate was concentrated in vacuo to afford a brown oil. Main peak in LC-MS, (8.01 g, 66% purity) and was taken through crude to the next transformation; m/z (LC-MS, ESP), RT=3.50 mins (M+H 284.3).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Cl.[NH2:13][CH2:14][CH2:15][SH:16]>C(O)C.O>[OH:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]2[NH:13][CH2:14][CH2:15][S:16]2)=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: NCCS
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C2NCCS2)ccc1O
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 66.7 %

Procedure:
To a solution of vanillin (2.0 g, 13.2 mmol) in ethanol (15 ml) was added dropwise a solution of cysteamine HCl (0.5 g, 4.4 mmol) in water (5 ml) and the solution stirred at RT for 16.5 h. The bulk of the ethanol was removed by rotary evaporator and the residue was diluted with water (15 ml) and extracted with diethyl ether (3×20 ml) to remove excess aldehyde. The aqueous layer was basified by addition of solid sodium carbonate (0.3 g) causing the product to precipitate out of solution. The precipitate was filtered, washed carefully with water (3×20 ml) and dried in a vacuum desiccator to give 2-(4-hydroxy-3-methoxyphenyl)-1,3-thiazolane (7) as a white solid (0.62 g, 67%), mp 158-161° (lit mp, 182-183°). 1H nmr (d6-dmso, 300 MHz) 2.8-3.0, m, H4,4,5; 3.12, br s, NH; 3.4-3.6, m, H5; 3.76, s, OMe; 5.34, s, H2; 6.70, d (8.0 Hz), H5′; 6.84, dd (1.8, 8.1 Hz), H6′; 7.04, d (1.8 Hz), H2′; 8.91, s, OH. ESI (+ve) MS m/z 212 (M+H, 100%).