Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][OH:24])=[CH:18][C:17]=1[O:25][CH3:26])(=[O:14])[CH3:13]>N1C=CC=CC=1.O>[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[CH:18][C:17]=1[O:25][CH3:26])(=[O:14])[CH3:13]
Reactant: COc1cc(CCO)ccc1OC(C)=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(CCOS(=O)(=O)c2ccc(C)cc2)ccc1OC(C)=O
Reaction time: 72 h

Procedure:
p-Toluenesulfonyl chloride (2.14 mL, 11.2 mmol) was added to a stirred solution of 4-(2-hydroxyethyl)-2-methoxyphenyl acetate (1.18 g, 5.61 mmol) in dry pyridine (20 mL) at 0° C. under N2. The reaction was stored at 4° C. for 3 days. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford 2-methoxy-4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)phenyl acetate, as an oil. Product was a 6:4 mixture of desired product and starting material but carried forward regardless. LCMS calc.=387.1; found=386.8 (M+Na)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.N[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:29]([NH:33]CCCC)CCC>>[CH2:29]([NH:33][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccn2cc(-c3ccc(OCCCCl)cc3)nc12
Reactant: Nc1ccccc1
Reactant: CCCCNCCCC
Product: Cc1cccn2cc(-c3ccc(OCCCNCc4ccccc4)cc3)nc12

Procedure:
This compound was prepared according to the procedure described in Example 1 of U.S. Pat. No. 4,727,145. using 2-(4-chloropropoxyphenyl)-8-methylimidazo[1,2-a]pyridine and aniline instead of 2-(4-chloropropoxyphenyl)-imidazo[1,2-a]pyridine and dibutylamine respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=2[N:17]=1.C1CCC(=C(F)CNCC2C=CC(F)=CC=2)CC1.[H-].[Na+].Cl[CH2:39][CH2:40][S:41][CH3:42]>O.CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:39][CH2:40][S:41][CH3:42])[C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=2[N:17]=1
Reactant: O=C1Nc2ccc(Cl)nc2Oc2ccccc21
Reactant: CSCCCl
Agent: FC(CNCc1ccc(F)cc1)=C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CSCCN1C(=O)c2ccccc2Oc2nc(Cl)ccc21
Temperature: 60 °C
Yield: 78.2 %

Procedure:
To as suspension of 17.0g (0.069 mole) 2-Chloropyrido[2,3-b][1,4]benzoxazepin-6(5H)-one and 150 mL of N,N-dimethylacetamide was added 9.8g of sodium hydride (50%). The mixture was warmed to 60° C. for 30 minutes. To the reaction mixture 12.2g (0.11 mole) of 2-chloroethylmethylsulfide was added dropwise. The mixture was heated to 120° C. for 4 hours, then cooled to room temperature and poured into water. The crude product was purified by column chromatography using silica gel and then recrystallized from petroleum ether/benzene to yield 17.3g (78% yield) of 2-chloro-5-(methylthioethyl)pyrido[2,3-b][1,4]benzoxazepin-6(5H)-one, m.p. 126°-128° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[N:14]#[C:15][NH2:16].Cl>C(O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:15]([NH2:16])=[NH:14])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: N#CN
Reactant: Cc1nccn1-c1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: Cc1nccn1-c1ccc(NC(=N)N)cc1
Yield: 64.4 %

Procedure:
To a solution of 4-(2-methyl-1H-imidazol-1-yl)aniline (2 g, 11.55 mmol) in ethanol (25 mL) was added cyanamide (0.728 g, 17.32 mmol) and hydrochloric acid (1.422 mL, 17.32 mmol). The reaction mixture was refluxed for 4 h. An additional 1 eq of hydrochloric acid (1.422 ml, 17.32 mmol) was added and precipitation occurred. The precipitated product was filtered off and washed with DCM to give 1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)guanidine (1.600 g, 64.4%). MS (ESI+)/(ESI−) m/z 216/214
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:34].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH2:18][CH3:19])=[N:15][C:16]([Cl:34])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[C:24]([F:32])[CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCl
Reactant: CCCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Solvent: CO
Product: CCCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
Subsequent chlorination (70° C.; 3h30) of 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-propyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (2.310 g; 5.071 mmol), and purification by FC (DCM/MeOH=50/1) afforded 1-chloro-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-propyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (1.130 g; 45%). LC-MS: tR=1.10 min.; [M+H]+=489.94 g/mol.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=2)[N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCOCC1>[NH3:3].[N+:12]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:25]1[CH2:24][C@@H:23]3[CH2:28][C@H:26]1[CH2:27][N:22]3[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH:11]=[CH:10]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc2cc([N+](=O)[O-])ccc2n1
Product: N

Procedure:
A mixture of 2-chloro-6-nitroquinoline [Lee B S, Lee B C, Jun J-G and Chi D Y; Heterocycles 1998 48 (12) 2637-2641] (2.1 g; 10 mmol), tert-butyl-(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (2.0 g; 10 mmol) and dioxane (50 ml) was stirred at reflux for 20 hours. The solvent was evaporated. Aqueous sodium hydroxide (50 ml; 1 M) was added, followed by extraction with diethyl ether (3×50 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as free base. Yield 1.6 g (43%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH:24]=O)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:15]=2[CH2:24][NH:31][CH2:30][C:29]([F:33])([F:32])[F:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: NCC(F)(F)F
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and 2,2,2-trifluoroethylamine hydrochloride.
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH:7]([C:12]([Br:15])([Br:14])[Br:13])[CH:8]=[C:9]([CH3:11])[CH3:10])=[O:5])=[N-]>C1(C)C=CC=CC=1.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[Br:13][C:12]([Br:15])([Br:14])[CH:7]1[CH:8]2[CH:3]([C:9]2([CH3:11])[CH3:10])[C:4](=[O:5])[O:6]1
Reactant: CC(C)=CC(OC(=O)C=[N+]=[N-])C(Br)(Br)Br
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)C2C(=O)OC(C(Br)(Br)Br)C21
Yield: 28 %

Procedure:
To a refluxing solution of cupric acetylacetonate (0.005 g, 0.019 mmole) in 40 ml of toluene was added dropwise over a period of 2.5 hours under an atmosphere of argon gas a solution of (±)-3-methyl-1-tribromomethyl-2-butenyl diazoacetate (0.203 g, 0.005 ml) in 10 ml of toluene. The mixture was then heated under reflux for one hour. After cooling, the reaction mixture was washed successively with two portions of 1 N aqueous hydrochloric acid, once with saturated aqueous sodium bicarbonate, and twice with saturated aqueous sodium chloride. After drying over magnesium sulfate, the solution was evaporated to give a yellow oil as the residue. The residue was purified by column chromatography on a silica gel column using 9/1 n-hexane/ethyl acetate as the eluent, yielding (±)-4-tribromomethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane (0.053 g, yield 28%); mp 101°-103° after recrystallization from n-hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[Br:10]Br>P([O-])([O-])(O)=O.[Na+].[Na+]>[Br:10][C:6]1[C:5]([CH3:9])=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: BrBr
Reactant: COc1cccc(C)n1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Product: COc1ccc(Br)c(C)n1
Yield: 57.9 %

Procedure:
2-Methoxy-6-methylpyridine (10 mL, 81 mmol) was suspended in a 0.15 mol//L disodium hydrogen phosphate aqueous solution (160 mL). Thereafter, a solution prepared by suspending bromine (4.15 mL, 81 mmol) in a 0.15 mol//L disodium hydrogen phosphate aqueous solution (160 mL) was added dropwise to the suspension at room temperature over 1 hour. The reaction solution was stirred at the same temperature as described above overnight. Thereafter, the reaction solution was extracted with methylene chloride (300 mL) three times. Organic layers were gathered. The resultant was dried over anhydrous magnesium sulfate and was then filtrated, followed by vacuum concentration. The obtained residue was distilled away under reduced pressure (91° C.-96° C./16 mmHg), so as to obtain 9.47 g of 3-bromo-6-methoxy-2-methyl-pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:3]=1.C(O)(C(F)(F)F)=O.[Cl:23][C:24]1[N:25]=[C:26](Cl)[C:27]2[CH2:33][N:32]([CH3:34])[CH2:31][CH:30]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:28]=2[N:29]=1.CCN(C(C)C)C(C)C>C(#N)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:26]2[C:27]3[CH2:33][N:32]([CH3:34])[CH2:31][CH:30]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[C:28]=3[N:29]=[C:24]([Cl:23])[N:25]=2)[CH:3]=1
Reactant: N#Cc1ccc(N)cc1OCCCCN
Reactant: CN1Cc2c(Cl)nc(Cl)nc2C(c2ccc(F)cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(NCCCCOc3cc(N)ccc3C#N)nc(Cl)nc2C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.72 %

Procedure:
A mixture of 4-amino-2-(4-aminobutoxy)benzonitrile, 2 TFA salt (Preparation X, 23.32 mg, 0.054 mmol), 2,4-dichloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Preparation V, 14 mg, 0.045 mmol) and DIEA (39.2 μL, 0.224 mmol) in acetonitrile (224 μL) was stirred at rt for 4 h. The crude product was purified by Prep-HPLC to obtain 4-amino-2-(4-((2-chloro-8-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)amino)butoxy)benzonitrile, (5.0 mg, 15.72% yield). LC-MS (M+Na)+=481.2. 1H NMR (500 MHz, methanol-d4) δ 7.26-7.18 (m, 3H), 7.16-7.08 (m, 2H), 6.33 (d, J=2.0 Hz, 1H), 6.28 (dd, J=8.5, 1.9 Hz, 1H), 4.45 (dd, J=10.5, 6.3 Hz, 1H), 4.30 (d, J=11.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.89 (dd, J=12.4, 6.3 Hz, 1H), 3.70-3.52 (m, 3H), 3.18-3.08 (m, 3H), 2.01-1.80 (m, 4H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([O:25][CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[CH:18][CH:17]=1)=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([O:25][CH2:26][CH:27]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
TFA (55.30 mL, 717.76 mmol, 15.0 eq) was added at 0° C. to a stirred solution of (tert-butoxy)-N-{4-[(fluoren-9-yl-methoxy)carbonylamino]phenyl}carboxamide (20.60 g, 47.85 mmol, 1.0 eq) in CH2Cl2 (900 mL). The resulting solution was allowed to come at room temperature. After stirring overnight at room temperature, the reaction mixture was concentrated to dryness and the residue was triturated in water. Then the mixture was filtered to afford 15.80 g of the expected crude product as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH2:12]([Li])[CH2:13][CH2:14][CH3:15].Br[C:18]1[CH:19]=[C:20]([C:25]2[N:30]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)[CH:28]=[C:27]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)[N:26]=2)[CH:21]=[C:22](Br)[CH:23]=1>O1CCCC1.CCCCCC.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>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:18]3[CH:19]=[C:20]([C:25]4[N:30]=[C:29]([C:31]5[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=5)[CH:28]=[C:27]([C:38]5[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=5)[N:26]=4)[CH:21]=[C:22]([C:13]4[CH:14]=[C:15]5[C:9](=[CH:4][CH:12]=4)[N:8]=[CH:7][CH:6]=[CH:5]5)[CH:23]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: Brc1ccc2ncccc2c1
Reactant: Cc1ccc(-c2cc(-c3ccc(C)cc3)nc(-c3cc(Br)cc(Br)c3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(-c2cc(-c3ccc(C)cc3)nc(-c3cc(-c4ccc5ncccc5c4)cc(-c4ccc5ncccc5c4)c3)n2)cc1
Temperature: 25 °C
Yield: 65 %

Procedure:
In a stream of argon, 0.34 g (1.62 mmol) of 6-bromoquinoline was dissolved in 7 mL of tetrahydrofuran, and then 1.03 mL of a solution of butyllithium 1.63 mmol in hexane was added dropwise at −78° C. The resultant mixture was stirred at −78° C. for 30 minutes, and then 0.41 g (1.63 mmol) of dichloro(tetramethylethylenediamine)zinc was added. The mixture was heated to room temperature and maintained at that temperature for 1 hour while being stirred. To the resultant mixture, 0.20 g (0.41 mmol) of 2-(3,5-dibromophenyl)-4,6-di-p-tolylpyrimidine, 19 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium and 3 mL of tetrahydrofuran were added, and the obtained suspension was heated under reflux for 17 hours. The reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. The thus-deposited solid was collected by filtration. The thus-obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:1) mixed solvent as an eluent to give 0.16 g of the target 2-[3,5-di(6-quinolyl)phenyl-4,6-di-p-tolylpyrimidine as a white solid (yield: 65%).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:19]([OH:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]>CN(C=O)C>[CH2:19]([O:25][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:7][CH2:6][CH:5]=[CH:4][CH:3]=[CH:2][CH3:16])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH:20]=[CH:21][CH:22]=[CH:23][CH3:24]
Reactant: CC=CC=CCO
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CC=CCOc1ccc(C(=O)c2ccc(OCC=CC=CC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
4,4'-Difluorobenzophenone (34) (4.8 grams, 22 mmol) was dissolved in anhydrous DMF (1 liter). NaH (95%; 5.6 grams, 220 mmol) was added and the solution was cooled to 0° C. 2,4-Hexadienol (5.8 mL, 51 mmol) was slowly added to the solution and the reaction mixture was allowed to warm to room temperature with stirring under argon overnight. The reaction mixture was concentrated in vacuo, dissolved in dichloromethane, and washed with water. The organic phase was dried (MgSO4) and concentrated and purified by column chromatography (silica gel; hexane/CH2Cl2, 1/3) to afford 2.07 grams (25%) of compound 35 as a white solid. 1H H NMR (300 MHz, DMSO-d6) δ1.73 (d, J=6.6 Hz, 6H), 4.68 (d, J=6.0 Hz, 4H), 5.69-5.84 (m, 4H), 6.05-6.19 (m, 2H), 6.31-6.45 (m, 2H), 7.08 (d, J=9.0 Hz, 4H), 7.68 (d, J=10.2 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:12])[CH2:10]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][C:14]([NH2:18])([CH2:16][CH3:17])[CH3:15]>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:12])[CH2:10][NH:18][C:14]([CH2:16][CH3:17])([CH3:15])[CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC(CBr)c1ccc(Cl)c(Cl)c1
Reactant: CCC(C)(C)N
Solvent: CCO
Product: CCC(C)(C)NCC(O)c1ccc(Cl)c(Cl)c1
Product: Cl
Reaction time: 48 h
Yield: 78 %

Procedure:
27 g (0.1 mol) of 1-(3,4-dichlorophenyl)-2-bromoethanol are added in the cold state to a solution of 37.5 g (50 ml) (0.43 mol) of 2-methyl-2-butylamine, 100 ml of ethanol and 0.5 g of KI. After 48 hours in contact at 20° C. and 3 hours under reflux, the mixture is filtered, the filtrate is evaporated under vacuum, the residue is taken up with ether and the organic phase is washed with water. 200 ml of N HCl are added, and the product is drained and washed with 20 ml of cold water and with ether. The hydrochloride (m.p.=184°-185° C.) is obtained in a 78% yield.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH2:6].[C:7]([NH:10][CH2:11][C:12]1([C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:9])[CH3:8].N1C=C[CH:31]=[CH:30][CH:29]=1>>[CH:30]([C:5]1[S:1][C:2]([NH:6][S:24]([C:21]2[CH:22]=[CH:23][C:18]([C:12]3([CH2:11][NH:10][C:7](=[O:9])[CH3:8])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[N:3][N:4]=1)([CH3:31])[CH3:29]
Reactant: c1ccncc1
Reactant: Nc1nncs1
Reactant: CC(=O)NCC1(c2ccc(S(=O)(=O)Cl)cc2)CCCCC1
Product: CC(=O)NCC1(c2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
600 mg of 5-isopropyl-(1,3,4-thiadiazol-2-ylamine were dissolved in 2 ml of pyridine. 1400 mg of 4-[1-(acetylamino-methyl)-cyclohexyl]-benzenesulfonyl chloride were added and the reaction mixture was stirred at room temperature for 15 hours. The pyridine was removed in vacuo and the residue coevaporated three times with portions of 100 ml toluene. The residue was purified by chromatography on silica gel with the eluents dichloromethane:methanol=95:5 to obtain 1.0 g of a light yellow oil.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O.[H][H].C(OCC)(=[O:23])C>[Pd].[Pd].[C]>[C:13]1([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([OH:23])[CH:5]=3)[NH:9][N:8]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CCOC(C)=O
Reactant: [H][H]
Agent: [Pd]
Product: Oc1ccc2[nH]nc(-c3ccccc3)c2c1
Temperature: 180 °C
Yield: 28 %

Procedure:
To a solution of 5-nitro-3-phenyl-1H-indazole (1.0 g, 4.2 mmol) in ethyl acetate (80 mL) was added palladium on activated carbon (Pd/carbon) then the reaction was subjected to an atmosphere of hydrogen. The reaction was stirred for 3 days when the Pd/carbon was filtered off and the solution concentrated to an oil under vacuo. The oil was then taken up in H2SO4 (6 mL) and water (60 mL) and the suspension was heated in a bomb to 180° C. for 2 days. The reaction was then cooled to room temperature, quenched with NaHCO3 (100 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined and dried (Na2SO4) and concentrated to recover the title compound (250 mg, 28% yield). 1H NMR (CDCl3) δ 13.0 (s, 1H), 9.20 (s, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.50 (t, 2H), 7.41 (d, 1H), 7.36 (t, 1H), 7.28 (s, 1H), 6.96 (dd, 1H); ES-MS (m/z) 195 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:21])=[O:17])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Nc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Reactant: CCCCCCCNC
Solvent: Cc1ccccc1C
Product: CCCCCCCN(C)C(=O)Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
Phenyl 4-fluoro-2-nitrophenylcarbamate (0.70 g) and N-methylheptylamine (0.33 g) were dissolved in xylene (5 ml) and the solution was heated under reflux for 2 hrs. The solvent was distilled off and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to give 1-(4-fluoro-2-nitrophenyl)-3-heptyl-3-methylurea as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=[C:11]3[C:16]([OH:17])=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.I[CH2:26][C:27]([F:30])([F:29])[F:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2ncn1CC(F)(F)F
Temperature: 100 °C

Procedure:
A mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-2A-1b: 1.20 g, 3.36 mmol), 2-iodo-1,1,1-trifluoroethane (705 mg, 3.36 mmol) and Cs2CO3 (2.19 g, 6.72 mmol) in DMF (20 ml) was heated at 100° C. for 17 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic solution was washed with saturated aqueous NaCl, dried, and concentrated in vacuo. The crude residue was purified via a Shimadzu HPLC system using a Waters XTERRA C18 50×50 mm column and a mixture of two solvent systems (0.1% NH4OH/CH3CN and H2O/0.1% NH4OH) to give the title compound 2A-1 (300 mg, 20%) as an amorphous solid: +ES MS (M+1) 439.1; 1H NMR (CDCl3) δ 7.87 (s, 1H), 7.54–7.30 (m, 8H), 4.7 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][OH:22]>CN(C=O)C.CCOC(C)=O>[OH:22][CH2:21][CH2:20][NH:19][C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCO
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)C(NCCO)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 98.8 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.10 g, 3.85 mmol) was dissolved in dry DMF (10 mL) under nitrogen atmosphere. 2-Aminoethanol (0.28 g, 4.62 mmol) was added followed by TEA (0.58 g, 5.77 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, dried with Na2SO4, filtered and evaporated. The residue was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant and TEA as additive affording the title compound (1.18 g, 99.1%). 1H NMR (500 MHz, CDCl3): δ 1.59 (d, 6H), 3.02 (q, 2H), 3.57 (t, 2H), 4.38-4.46 (m, 1H), 5.71 (bs, 1H), 7.43-7.46 (m, 3H), 7.50-7.53 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 20.38, 46.11, 47.76, 60.78, 107.46, 125.22, 128.96, 129.89, 131.70, 135.84, 158.67; Mass Spectrum: M+H+ 311.