Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:30])([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(c1ccccc1)c1ccccc1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with aminodiphenylmethane (42 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 66 mg of the title compound as a colorless solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:13][NH2:14])[CH:6]=[CH:7][C:8]=1[S:9](=[O:12])(=[O:11])[NH2:10].[F:15][C:16]([F:35])([F:34])[C:17](=O)[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[C:23]([Cl:32])[CH:22]=1)=O>>[Cl:32][C:23]1[CH:22]=[C:21]([C:19]2[N:13]([C:5]3[CH:6]=[CH:7][C:8]([S:9]([NH2:10])(=[O:11])=[O:12])=[C:3]([F:2])[CH:4]=3)[N:14]=[C:17]([C:16]([F:35])([F:15])[F:34])[CH:18]=2)[CH:26]=[CH:25][C:24]=1[C:27]1[O:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(-c2ccco2)c(Cl)c1
Reactant: NNc1ccc(S(N)(=O)=O)c(F)c1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3ccco3)c(Cl)c2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 60 using 3-fluoro-4-sulfamoylphenylhydrazine hydrochloride instead of 3-fluoro-4-(methylsulfonyl)phenylhydrazine hydrochloride and 4,4,4-trifluoro-1-[3-chloro-4-(2-furyl)phenyl]butane-1,3-dione instead of 4,4,4-trifluoro-1-[4-(2-furyl)phenyl]butane-1,3-dione in step 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1([CH3:45])[C:43](O)=[CH:42][CH:41]=[CH:40][CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:45])[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Reactant: Cc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccccc2C)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 2.97 g of o-cresol and 250 ml of anhydrous benzene is added, dropwise at 5° C. under nitrogen over a 90 minute period, a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete the mixture is stirred overnight at room temperature. The solid is then filtered and washed with benzene and the filtrate concentrated in vacuo to an oil. The oil is triturated overnight in a stoppered flask with 250 ml of hexane. The hexane is decanted and the gummy solid is triturated with more hexane and the hexane solution is filtered. The hexane filtrate is washed with 10% aqueous sodium hydroxide solution (3×75 ml), 2 N hydrochloric acid (100 ml), water (100 ml), saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a yellow gum. The gummy solid previously obtained is washed with ether. The ether filtrate is concentrated in vacuo and the residue is partitioned between 150 ml of hexane and 50 ml of 10% sodium hydroxide solution. The phases are separated. The hexane phase is washed with 10% sodium hydroxide solution, followed by 2 N hydrochloric acid solution (50 ml), water (100 ml), saturated sodium chloride solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting gum is combined with the previously obtained gum. Trituration of the gum with a 2:1 mixture of petroleum ether:ether affords a colorless solid. A second crop is obtained from the filtrate. Filtration through a silica gel plug using dichloromethane as solvent, followed by trituration with 2:1/petroleum ether:ether solution and filtration affords product as a colorless solid, mp 119.5°-121° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9].[N-:21]=[N+:22]=[N-:23].[Na+].CCOC(C)=O>CN(C=O)C>[N:21]([C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]=1[C:8]#[N:9])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(-c2ccc(Cl)cc2Cl)cn2ccnc2c1N=[N+]=[N-]
Temperature: 60 °C
Yield: 96 %

Procedure:
A mixture of 8-chloro-6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridine-7-carbonitrile (80 mg, 0.25 mmol, prepared according to Example 23, Step 12.2) and sodium azide (81 mg, 1.24 mmol) in DMF (1 mL) was stirred and heated at 60° C. for 3 h. The reaction mixture was cooled to RT, poured into AcOEt and washed successively with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated to yield the crude title compound (77.4 mg, 0.24 mmol, 95%) as a brownish solid, which was used in the next step without further purification. MS: 329 [M+1]+; HPLC: AtRet=2.56.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K+].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH-:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN1CCCC1=O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:22][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=2)(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: CNc1nc(Cl)cc(Cl)n1
Reactant: [NH-]S(=O)(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(Cl)cc2)n1
Yield: 84.6 %

Procedure:
0.39 g (0.0022 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 1.0 g (0.0044 mol) of 4-chloro-benzene-sulfonamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was saturated with sodium chloride, evaporated briefly in a vacuum, made acid with 4N HCl and extracted with dichloromethane. The two extracts were combined and chromatographed over silica gel with cyclohexane/ethyl acetate 1:1 as the eluent. There was obtained 0.62 g (85%) of 4-chloro-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals. m.p. 196-198° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[CH2:12]([N:14]1[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]1SC)[CH3:13].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][C:15]1[N:14]([CH2:12][CH3:13])[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[N:16]=1
Reactant: Nc1cc(Cl)ccc1Cl
Reactant: CCn1c(SC)nc(C(F)(F)F)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(Nc2cc(Cl)ccc2Cl)nc(C(F)(F)F)cc1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
2,5-Dichloroaniline (0.49 g, 3.0 mmol) was dissolved in DMF (20 ml), and sodium hydride (60% oil, 0.20 g, 5.01 mmol) was added, followed by stirring at room temperature for 20 minutes. Then, 3-ethyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (1,14 g, 4.80 mmol) synthesized in the above was added, followed by stirring at 80° C. for 4 hours. After completion of the reaction, ice-water (30 ml) and ethyl acetate (30 ml) were added to the reaction solution to separate the organic layer, and then the aqueous layer was extracted with ethyl acetate (20 ml×3). The organic layers were combined, washed with saturated sodium bicarbonate aqueous solution (50 ml), water (50 ml×2) and saturated brine (80 ml) and then dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. The thus obtained crude product was purified by a silica gel column chromatography (hexane: ethyl acetate=10:1) and then recrystallized from toluene, thereby obtaining yellow crystals of 2-(2,5-dichlorophenyl)amino-3-ethyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 6].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[C:29](=[O:30])[NH:28][C:27](=[O:31])[C:26]([C:32](NC(=O)OCC)=[O:33])=[N:25]2)[CH:5]=[C:6]([Cl:23])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:10])[CH3:9].C(O)(=[O:42])C>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[C:29](=[O:30])[NH:28][C:27](=[O:31])[C:26]([C:32]([OH:33])=[O:42])=[N:25]2)[CH:5]=[C:6]([Cl:23])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:9])[CH3:10]
Reactant: CCOC(=O)NC(=O)c1nn(-c2cc(Cl)c(C(C)(C)c3noc(-c4ccccc4C)n3)c(Cl)c2)c(=O)[nH]c1=O
Reactant: CC(=O)O
Agent: Cl
Product: Cc1ccccc1-c1nc(C(C)(C)c2c(Cl)cc(-n3nc(C(=O)O)c(=O)[nH]c3=O)cc2Cl)no1

Procedure:
A mixture of intermediate (21) (0.0302 mole) in HCl 36% (10 ml) and acetic acid (200 ml) was stirred and refluxed overnight. The reaction mixture was poured out onto crushed ice and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated, yielding 16.3 g of 2-[3,5-dichloro-4-[1-[5-[2-methylphenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl]phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid (intermediate 22).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C(C)=[O:20])(F)(F)F.OO>C([O-])([O-])=O.[K+].[K+]>[CH:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[O:20][C@@H:8]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Reactant: CC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Product: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 310.8 %

Procedure:
To a mixture of suspension of trans-stilbene (18.02 g, 0.1 mol) and CF3COCH3 (3.36 g, 0.03 mol) in CH3CN-DMM (½ v/v, 750 mL) and aqueous K2CO3 (1.5 M in 4×10−4 M EDTA, 150 mL) was added H2O2 (30%, 40 mL, 0.4 mol) at 0° C. Upon stirring at 0° C. for 1 h and at room temperature for 5 h, the reaction mixture was extracted with hexane (3×500 mL). The combined organic layers were washed with aqueous Na2S2O3 (1 M) (3×50 mL) and brine (100 mL), dried (Na2SO4), filtered, concentrated, and purified by flash chromatography on silica gel (buffered with 1% NEt3) using hexane-ether as eluent to give trans-stilbene oxide as a white solid (18.3 g, 93.3%).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[C:12]([O:18][CH3:19])[CH:11]=1.N1C=CN=C1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1cc(Br)ccc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(Br)ccc1CO[Si](C)(C)C(C)(C)C
Yield: 66.1 %

Procedure:
tert-Butyldimethylsilyl chloride (1.04 g, 6.9 mmol) was added to a mixture of (4-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mol) and imidazole (470 mg, 7.0 mmol) in DMF (15 mL) and the resultant mixture was stirred at ambient temperature for 66 h. The mixture was concentrated to about a third of the original volume then diluted with water and extracted with diethyl ether (×3). The combined organic layer was dried over magnesium sulfate, filtered and evaporated. The resultant residue was purified by chromatography (silica, 50 g column, Si-SPE, 5% diethyl ether in pentane) to afford the title compound as a colourless oil (1.51 g, 98%). 1H NMR (CDCl3, 400 MHz): 7.34 (dt, J=8.1, 1.05 Hz, 1H); 7.11 (dd, J=8.1, 1.8 Hz, 1H); 6.95 (d, J=1.8 Hz, 1H); 4.69 (d, J=1.0 Hz, 2H); 3.81 (s, 3H); 0.97-0.94 (m, 9H); 0.13-0.08 (m, 6H).
Reaction SMILES: N1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[C:8](=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[CH:12][CH:11]=[N:10]4)[N:7]=2)=[N:4][N:3]=N1.[C:20]1([C:32](Cl)=[O:33])[CH:25]=[C:24]([C:26](Cl)=[O:27])[CH:23]=[C:22]([C:29](Cl)=[O:30])[CH:21]=1>N1C=CC=CC=1>[N:7]1[C:8]2[C:17](=[CH:16][CH:15]=[C:14]3[C:9]=2[N:10]=[CH:11][CH:12]=[CH:13]3)[CH:18]=[CH:19][C:6]=1[C:5]1[O:33][C:32]([C:20]2[CH:25]=[C:24]([C:26]3[O:27][C:5]([C:6]4[CH:19]=[CH:18][C:17]5[C:8](=[C:9]6[C:14](=[CH:15][CH:16]=5)[CH:13]=[CH:12][CH:11]=[N:10]6)[N:7]=4)=[N:4][N:3]=3)[CH:23]=[C:22]([C:29]3[O:30][C:5]([C:6]4[CH:19]=[CH:18][C:17]5[C:8](=[C:9]6[C:14](=[CH:15][CH:16]=5)[CH:13]=[CH:12][CH:11]=[N:10]6)[N:7]=4)=[N:4][N:3]=3)[CH:21]=2)=[N:3][N:4]=1
Reactant: c1cnc2c(c1)ccc1ccc(-c3nnn[nH]3)nc12
Reactant: O=C(Cl)c1cc(C(=O)Cl)cc(C(=O)Cl)c1
Solvent: c1ccncc1
Product: c1cnc2c(c1)ccc1ccc(-c3nnc(-c4cc(-c5nnc(-c6ccc7ccc8cccnc8c7n6)o5)cc(-c5nnc(-c6ccc7ccc8cccnc8c7n6)o5)c4)o3)nc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
To a flask was added a mixture of 15 g 2-(1H-tetrazol-5-yl)-[1,10]phenanthroline and 300 ml pyridine. The mixture was then heated to 80-90° C., and 4.86 g 1,3,5 benzene tricarbonyl chloride was added. Subsequently, the mixture solution was heated to 110° C. and stirred overnight. After completion of reaction, as shown in scheme 8, the reaction mixture was filtered to collect solids. The solids was washed by pyridine and CH2Cl2 respectively, and then dried on oven to obtain products 6.6 g (yield=44.1%). MS(m/z, FAB+), 888, 810, 521, 444, 155.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:10]([O:9][C:3]1[C:2]([Cl:1])=[CH:7][NH:6][C:5](=[O:8])[CH:4]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Product: O=C(Oc1cc(=O)[nH]cc1Cl)c1ccccc1
Yield: 37 %

Procedure:
Using 1.00 g of 5-chloro-4-hydroxy-2-pyridone and 0.96 ml of benzoyl chloride and following the general procedure of Example 9, 0.64 g of the title compound was produced in a yield of 37%. M.p. 196°-197° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].[H-].[Na+].Cl[C:13]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:16][S:15][N:14]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:13]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[N:16][S:15][N:14]=1)[CH3:2]
Reactant: CCOCCOCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-ethoxyethoxy)ethanol (1.21 g, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.O=S(Cl)[Cl:13]>>[F:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1F
Product: O=C(Cl)c1cccnc1F

Procedure:
2-Fluoropyridine-3-carboxylic acid (7 g, Step C) was suspended in SOCl2 (100 mL). After heating under reflux for 2 h, the mixture became homogeneous. Excess SOCl2 was removed in vacuo to afford a brown solid as desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][C:44]([Cl:46])=[CH:45][C:37]=4[Cl:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-amino-benzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.76 g of 2,4-dichlorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.39 g of the desired product as a crystalline solid, m.p. 212°-214° C.
Reaction SMILES: [CH2:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1)[CH:2]=[CH2:3].[OH2:16].[OH-].[Na+].OO>C1COCC1>[C:10]1([C:4]2([CH2:1][CH2:2][CH2:3][OH:16])[CH2:9][CH2:8][CH2:7][CH2:6][O:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CCC1(c2ccccc2)CCCCO1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-allyl-2-phenyltetrahydro-2H-pyran (700 mg, 3.46 mmol) in THF (7 mL) at 0° C. was added 1M borane tetrahydrofuran complex (1.730 mL, 1.730 mmol) dropwise, and the mixture was stirred overnight at room temperature. After cooling to 0° C., water (0.07 ml) was added to destroy the excess borane. After stirring for mins, 3M NaOH (0.42 mL, 1.260 mmol) was added and stirred for 10 mins. Then 30% H2O2 (0.42 mL, 4.11 mmol) was added and the cooling bath was removed. It was refluxed for 1.5 hrs and cooled to room temperature. It was extracted with EtOAc (2×), and the combined extracts were washed with brine, dried over Na2SO4 and evaporated to give 3-(2-phenyltetrahydro-2H-pyran-2-yl)propan-1-ol as oil. 1H NMR (400 MHz, CCl3D) δ ppm 7.11-7.44 (5H, m), 3.66-3.81 (2H, m), 3.48-3.59 (2H, m), 2.22-2.37 (2H, m), 1.35-1.89 (8H, m).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:10]>>[NH:10]=[C:3]([CH3:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)CC(C)=N
Yield: 85 %

Procedure:
A solution of ethyl acetoacetate (50 g, 385 mmol, 1.0 eq) in 25% aqueous ammonia (300 mL) was stirred at room temperature for 1 h then extracted with EtOAc (2×300 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure to give ethyl 3-iminobutanoate (42 g, 85%) as a yellow oil, which was used directly in the next step.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([CH3:10])([CH3:9])[C:3]1=[O:11].C1C=CC=CC=1.[CH2:18](O)[CH:19]([CH3:21])[CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])([CH3:9])[CH2:5][CH2:6][C:7]=1[O:8][CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CO
Reactant: CC1C(=O)C=CC(C)(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1=C(OCC(C)C)CCC(C)(C)C1=O
Temperature: 25 °C

Procedure:
The compound 2,6,6-trimethylcyclohexen-1,3-dione (43.6 g) was added to a mixture of benzene (250 ml), isobutanol (50 ml) and PTSA (500 mg) and heated under reflux for 3 hr in conjunction with a Dean and Stark water separator. The reaction was then cooled to room temperature, washed with aqueous sodium carbonate solution and brine and taken to dryness "in vacuo". Distillation of residue through a 6 inch vacuum jacketed vigreaux column yielded pure 2,6,6-trimethyl-3-isobutoxycyclohex-2-en-1 one (54.6 g) bp 104°-107°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:1][C:2]2[CH:7]=[N:6][C:5]([Br:8])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)nc2)CC1
Yield: 57.6 %

Procedure:
Using general procedure A, 5-amino-2-bromopyridine (Binz; v, Schickh, Chem. Ber., 68, 1935, 315-321) (308 mg, 1.78 mmol) and 1-Boc-4-piperidone (317 mg, 1.59 mmol) gave 4-(6-bromo-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid (326 mg, 58%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].OS(O)(=O)=O.[CH2:13](O)[CH3:14]>>[C:1]([O:7][CH2:13][CH3:14])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: CCO
Reactant: C#CCCC(=O)O
Agent: O=S(=O)(O)O
Product: C#CCCC(=O)OCC
Temperature: 50 °C
Yield: 70 %

Procedure:
In analogy to the method as described in Tetrahedron, 2000, 56, 5735-5742, a mixture of the 4-pentynoic acid (10 g, 102 mmol) and H2SO4 98% (0.338 mL, 6.12 mmol) in ethanol (113 mL) was heated at 50° C. overnight. The reaction mixture was concentrated and the crude product was dissolved in ethyl acetate, washed with NaHCO3 1M and water. The solvent was removed under reduced pressure to afford 9.04 g of ethyl pent-4-ynoate (Yield: 70%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1.[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>CN(C)C(=O)C>[Cl:11][CH2:12][CH2:13][C:14]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1)=[O:15]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc2ncnn2n1
Solvent: CC(=O)N(C)C
Product: O=C(CCCl)Nc1ccc2ncnn2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Amino[1,2,4]triazolo[1,5-b]pyridazine (0.80 g) was dissolved in N,N-dimethylacetamide (7 ml), followed by addition of 3-chloropropionylchloride (0.68 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour and poured into ice-water, followed by extraction with a mixture of ethyl acetate and tetrahydrofuran (1:1). The extract was washed with an aqueous sodium chloride saturated solution, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl ether was added to the residue. The resulting crystals were collected by filtration and dried to yield the title compound (0.875 g).