Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[CH:12]1([C:15](Cl)=[O:16])[CH2:14][CH2:13]1.N1C=CC=CC=1>CCOCC>[CH:12]1([C:15]([O:11][CH2:10][CH2:9][S:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:16])[CH2:14][CH2:13]1
Reactant: OCCSc1ccc(Cl)cc1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(OCCSc1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 1.88 g. 2-(4-chlorophenylthio)ethanol and 1.35 g. cyclopropylcarboxylic acid chloride in 50 ml. ether is added 2 equivalents pyridine. The reaction mixture is stirred overnight at room temperature and worked up as in Example 5 to yield 2-(4-chlorophenylthio)ethyl cyclopropanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C.S(OC)(OC)(=O)=O>CN(C=O)C>[CH3:29][O:16][C:7]1[N:8]=[C:9]([CH3:15])[C:10]2[C:5]([C:6]=1[CH2:17][C:18]1[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=1)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: COc1cc2c(C)nc(O)c(Cc3ccc4ccccc4c3)c2cc1OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COc1cc2c(C)nc(OC)c(Cc3ccc4ccccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6,7-dimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinolin-3-ol CCH 29038 free base (58 mg, 161 μmol) in dry DMF (6 mL) at 0° C. in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added LiHMDS (1.0 N in TBME, 175 μL, 175 μmol) and the mixture was stirred for 20 min at RT. Dimethyl sulphate (18 μL, 192 μmol) was then added at 0° C. and the mixture was stirred overnight at RT. The mixture was then concentrated to dryness at 40° C. under vacuum and the residue was taken up in CH2Cl2 (40 mL). The organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 86:14) provided 23 mg of 3,6,7-trimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinoline. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.50 M HCl solution in MeOH (0.4 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 3,6,7-trimethoxy-1-methyl-4-(naphthalen-2-ylmethyl)isoquinoline hydrochloride 18 as a brown solid (25 mg, 38% yield).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:26][CH:27]=[CH2:28])[CH:8]([CH3:25])[CH2:9][CH2:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:16][CH:15]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].NN>C(O)COCCO>[CH:1]1([CH2:6][N:7]([CH2:26][CH:27]=[CH2:28])[CH:8]([CH3:25])[CH2:9][CH2:10][CH2:11][CH2:12][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:18][CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCN(CC1CCCC1)C(C)CCCC(=O)c1ccc(-n2ccnc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Product: C=CCN(CC1CCCC1)C(C)CCCCc1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Example 28, react 5-[(cyclopentylmethyl)(2-propenyl)amino]-1-[4-(1H-imidazol-1-yl)-phenyl]hexan-1-one with potassium hydroxide and hydrazine in diethylene glycol to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][CH3:16])[C:11](F)=[O:12].C(N(CC)CC)C.C(OC(C)C)(C)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][CH3:16])[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: CSSN(C)C(=O)F
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: CSSN(C)C(=O)ON=C1SCOC1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 1.9 %

Procedure:
To a solution of 4.22 g (0.032 m) of 5-methyl-4-oximino-1,3-oxathiolane and 5.0 g (0.032 m) of N-methyl-N-(methylthiosulfenyl) carbamoyl fluoride in 25 ml of dioxane was added 3.25 g (0.032 m) of triethylamine. After stirring at room temperature for 19 hrs. the reaction mixture was quenched with 100 ml of water and extracted in ethyl acetate. After the usual work-up it yielded a residual oil. Addition of isopropyl ether resulted in the precipitation of 0.16 g of a solid biscarbamate. The concentrated filtrate was purified by column chromatography to yield 2.97 g of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:18]2[CH2:19][CH2:20][N:15]([S:12]([CH3:11])(=[O:14])=[O:13])[CH2:16][CH2:17]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(Cl)c1ccc(Br)cc1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(c1ccc(Br)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 65 °C

Procedure:
1-Bromo-4-(1-chloroethyl)benzene (3.46 g, 15.8 mmol), 1-methanesulfonylpiperazine (5.19 g, 31.6 mmol) and diisopropylethylamine (11.8 mL, 79 mmol) were stirred in acetonitrile (125 mL) and heated to 65° C. for 3 d. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with sat. NaHCO3 (aq.). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography using silica gel and eluting with 100% isohexanes to 100% EtOAc to give the title compound.
Reaction SMILES: O=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6]CC)=O.C1(NN)C=CC=CC=1.[CH:19]1([C:22]2[N:26]([CH:27](C)C)[N:25]=[CH:24][C:23]=2C=O)[CH2:21][CH2:20]1>>[CH2:9]([C:2]1[N:25]([C:24]2[CH:20]=[CH:21][CH:19]=[CH:22][CH:23]=2)[N:26]=[CH:27][C:3]=1[CH:4]=[O:6])[CH3:10]
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Reactant: CCOC(=O)CC(=O)CC
Solvent: NNc1ccccc1
Product: CCc1c(C=O)cnn1-c1ccccc1

Procedure:
5-Ethyl-1-phenyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl 3-oxo-pentanoate and phenyl hydrazine in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:25])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([Br:22])[N:19]=[C:20](Br)[C:15]4=[N:14][C:13]=3[CH2:23][OH:24])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[CH3:26][CH:27]([CH3:30])[CH2:28][NH2:29].C1(C)C=CC=CC=1>CN(C)C=O>[Br:22][C:18]1[N:19]=[C:20]([NH:29][CH2:28][CH:27]([CH3:30])[CH3:26])[C:15]2[N:16]([C:12]([C:9]3[CH:8]=[CH:7][C:6]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:25])=[CH:11][CH:10]=3)=[C:13]([CH2:23][OH:24])[N:14]=2)[CH:17]=1
Reactant: CC(C)CN
Reactant: O=C(NC1CC1)c1ccc(-c2c(CO)nc3c(Br)nc(Br)cn23)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)CNc1nc(Br)cn2c(-c3ccc(C(=O)NC4CC4)cc3)c(CO)nc12
Temperature: 23 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of 50 mg (107 μmol) N-cyclopropyl-4-[6,8-dibromo-2-(hydroxymethyl)imidazo[1,2-a]pyrazin-3-yl]benzamide in 0.71 mL N,N-dimethylformamide were added 32 μL 2-methylpropan-1-amine and the mixture was stirred at 23° C. for 3 hours. Toluene was added and the solvents removed. The residue was purified by chromatography to give 40.7 mg (83%) of the title compound. 1H-NMR (300 MHz d6-DMSO): δ=8.52 (1H, d), 8.12 (1H, t), 7.95 (2H, d), 7.68 (2H, d), 7.50 (1H, s), 5.18 (1H, t), 4.46 (2H, d), 3.23 (2H, m), 2.85 (1H, m), 2.00 (1H, m), 0.87 (6H, m), 0.68 (2H, m), 0.55 (2H, m) ppm. UPLC-MS: RT=1.18 min; m/z 459.4 [MH+]; required MW=458.4.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:46]([NH:48][CH3:49])=[O:47])[N:8]([C:32]4[CH:37]=[CH:36][C:35]([NH:38][C:39]5[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=5)=[CH:34][CH:33]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.NCCN(S(C)(=O)=O)C1C(C2CC2)=CC2C(C=1)=NN(C1C=CC(Br)=CC=1)C=2C(NC)=O>>[NH2:21][CH2:20][CH2:19][CH2:18][N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:12]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]2[C:10]([CH:11]=1)=[N:9][N:8]([C:32]1[CH:33]=[CH:34][C:35]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:36][CH:37]=1)[C:7]=2[C:46]([NH:48][CH3:49])=[O:47]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1
Agent: CNC(=O)c1c2cc(C3CC3)c(N(CCN)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCN)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1

Procedure:
6-[3-Aminopropyl(methylsulfonyl)amino]-5-cyclopropyl-2-[4-(4-fluoroanilino)phenyl]-N-methyl-indazole-3-carboxamide (iv) was prepared by hydrolysis of compound (iii) using a similar procedure to Compound (7) (Method D, Step b).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[O:6])[CH3:5].[CH:8]1([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH3:25])[C:17]([C:26](=[S:28])[NH2:27])=[CH:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH3:25])[C:17]([C:26]3[S:28][CH:2]=[C:3]([C:4](=[O:6])[CH3:5])[N:27]=3)=[CH:16]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(=O)C(=O)CCl
Reactant: COc1cccc2c(C(N)=S)cn(CC3CCCCC3)c12
Solvent: CCO
Product: COc1cccc2c(-c3nc(C(C)=O)cs3)cn(CC3CCCCC3)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.9 %

Procedure:
A solution of 1-chloro-2,3-butanedione (0.717 g, 5.95 mmol) in ethanol (3 ml) was added dropwise to a solution of 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbothioic acid amide (prepared as in Example 16; 1.20 g, 3.97 mmol) in ethanol (12 ml) at room temperature, and then the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and the obtained residue was mixed with dichloromethane (50 ml) and washed sequentially with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with 33% (v/v) ethyl acetate in n-heptane to afford 1-{2-[1-(cyclohexyl)methyl-7-methoxy-1H-indol-3-yl]thiazol-4-yl}ethanone as a brown solid (1.11 g).
Reaction SMILES: [C:1]([C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][NH:13][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:21]SC1C(C2C=NC=CC=2)=NNC=1>>[C:1]([C:10]1[C:11]([C:15]2[CH2:16][N:17]([CH3:21])[CH2:18][CH2:19][CH:20]=2)=[N:12][NH:13][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCCCCCC#Cc1c[nH]nc1-c1cccnc1
Product: CCCCCCCC#Cc1c[nH]nc1C1=CCCN(C)C1
Yield: 79 %

Procedure:
Compound 44C was converted to compound 45C, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 79% (amorphous). LCMS (method A); Rt: 2.17 min, ([M+H]+=286). 1H-NMR (400 MHz, CDCl3): δ 7.57 (s, 1H), 6.74-6.69 (bs, 1H), 3.40-3.36 (m, 2H), 2.58 (bt, J=7 Hz, 2H), 2.44 (s, 3H), 2.43-2.36 (m, 2H), 1.63-1.55 (m, 2H), 1.48-1.39 (m, 2H), 1.36-1.23 (m, 6H), 0.89 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:16]2[C:21]([CH3:22])=[C:20]([O:23]C)[C:19]([CH3:25])=[C:18]([CH3:26])[C:17]=2[O:27]C)O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:14][C:16]3[C:21]([CH3:22])=[C:20]([OH:23])[C:19]([CH3:25])=[C:18]([CH3:26])[C:17]=3[O:27]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1c(C)c(C)c(OC)c(C(O)C2CCN(Cc3ccccc3)CC2)c1C
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)CC1(CCN(Cc3ccccc3)CC1)O2
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of (1-benzyl-4-piperidyl)(2,5-dimethoxy-3,4,6-trimethylphenyl)methanol (6.10 g, 15.9 mmol) in acetic acid (30 mL) was added 48% hydrobromic acid (40 mL), and the mixture was heated under reflux for 15 hours in an argon atmosphere. The reaction mixture was cooled to room temperature, made basic with 8N sodium hydroxide solution, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (4.60 g, yield 86%). This was amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(C1C=C(C)C(C(N)=O)=NC=1)#[N:14]>>[Cl:1][C:2]1[C:3]([C:10]([NH2:14])=[O:12])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Reactant: Cc1cc(C#N)cnc1C(N)=O
Product: N#Cc1cnc(C(N)=O)c(Cl)c1

Procedure:
3-Chloro-5-cyano-pyridine-2-carboxylic acid amide was prepared from 3-chloro-5-cyano-pyridine-2-carboxylic acid (CAS 1200497-81-9) in analogy to the procedure described for Amide 1.
Reaction SMILES: [CH:1]1([N:7]([CH3:28])[C:8]2[C:9]3[CH:17]=[CH:16][N:15]([Si](C(C)C)(C(C)C)C(C)C)[C:10]=3[N:11]=[CH:12][C:13]=2[F:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:1]1([N:7]([CH3:28])[C:8]2[C:9]3[CH:17]=[CH:16][NH:15][C:10]=3[N:11]=[CH:12][C:13]=2[F:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N(C)C3CCCCC3)c(F)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(c1c(F)cnc2[nH]ccc12)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution N-cyclohexyl-5-fluoro-N-methyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (50 mL) in tetrahydrofuran (0.7 mL) was added tetra-n-butylammonium fluoride (0.372 mL, 1.0M in tetrahydrofuran) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours, then another 3 equivalent of tetra-n-butylammonium fluoride (0.372 mL) was added. The mixture was heated at 50° C. for 2 hours, at reflux for 6 hours. After cooling to ambient temperature, the mixture was concentrated. The residue was purified by column chromatography (gradient elution, n-hexane to 1:1 n-hexane/EtOAc) to give N-cyclohexyl-5-fluoro-N-methyl-1H-pyrrolo[2,3-b]pyridin-4-amine (10 mg) as a pale yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]2[CH:12]=[N:13]C(C#N)=[C:10]2[N:9]=[CH:8][CH:7]=1.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]2[CH:12]=[N:13][C:19]([C:18]([OH:21])=[O:20])=[C:10]2[N:9]=[CH:8][CH:7]=1
Reactant: N#Cc1ncn2c(-c3cccs3)ccnc12
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)c1ncn2c(-c3cccs3)ccnc12

Procedure:
A mixture of 0.01 mol of 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8-carbonitrile (Example 1), 15 ml. of glacial acetic acid and 15 ml. of concentrated hydrochloric acid can be refluxed for 16 hours. The reaction mixture can be cooled and evaporated to dryness in vacuo, water added, and the precipitated solid recovered by filtration to produce 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12](I)[CH:13]=[CH:14][CH:15]=1.CC(CCC)C(=O)C(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.Cl[Cu].CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:9])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: Clc1cccc(I)c1
Agent: Cl[Cu]
Agent: CCCC(C)C(=O)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Clc1cccc(Sc2ccc(Br)cc2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
N-Methyl-2-pyrrolidone (10 mL) was added to 4-bromothiophenol (0.500 g, 2.64 mmol) in a sealed tube and the mixture was purged with argon for 5 minutes. After this time, 3-chloro-iodobenzene (0.63 g, 2.64 mmol), CuCl (0.131 g, 1.32 mmol), tetramethyl heptanedione (0.14 mL, 0.66 mmol) and cesium carbonate (1.70 g, 5.28 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130° C. under argon for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a celite bed. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the crude product. Silica gel chromatography (neat hexanes) provided impure 1-bromo-4-(3-chlorophenylsulfanyl)-benzene (0.7 g). MS calcd. for C12H7BrClS [M−H] 298, obsd. 298.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22](=O)[O:23]C(C)=C)[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[N:29]1CCOCC1.N.CO>C1COCC1>[N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([NH2:29])=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN1CCOCC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Temperature: 55 °C
Reaction time: 5 h
Yield: 614.9 %

Procedure:
To a solution of prop-1-en-2-yl 6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-ylcarbamate (109 mg, 0.298 mmol) and 4-methylmorpholine (3.3 μL, 0.030 mmol) in dry THF (27 mL) was added a solution of NH3 in MeOH (0.6 mL, 1M, 0.6 mmol) and the reaction mixture heated to 55° C. Further aliquots of the methanolic NH3 solution were added after 1 hr (0.6 ml, 0.6 mmol) and after 5 hr (1.0 mL, 1 mmol) and after a further 16 hr the reaction mixture was evaporated in vacuo. The residue was taken up into THF (3.0 mL) and NMM (3.3 μL, 0.030 mmol) and NH3 in MeOH (0.6 mL, 1M, 0.6 mmol) were added and the reaction mixture was heated to 55° C. Further aliquots of the methanolic NH3 solution (1M, 1.0 mL, 1.0 mmol) were added after 2 hr and after 3 hr. After 3.5 hr additional aliquots of NMM (3.3 μL, 0.030 mmol) and methanolic NH3 (1M, 1.0 mL, 1.0 mmol) were added and the reaction mixture was maintained at 55° C. for 15 hr. The reaction mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 4 g, EtOAc in isohexane, 0-100%, gradient elution) to afford the title compound as a yellow solid (60 mg, 61%); Rt 1.87 min (Method 2); m/z 326 (M+H)+ (ES+).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC(C)([O-])C.[Na+].[CH2:26]([O:28][C:29](=[O:35])[CH:30]=[CH:31]OCC)[CH3:27].[C:36]1([S:42]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2Br)(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.P([O-])(O)(O)=O.[K+]>O1CCCC1.C(OC)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:26]([O:28][C:29]([C:30]1[C:47]2[C:46](=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]([S:42]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:44])=[O:43])[CH:31]=1)=[O:35])[CH3:27]
Reactant: O=S(=O)(Cc1ccccc1Br)c1ccccc1
Reactant: CCOC=CC(=O)OCC
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1=CC(S(=O)(=O)c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 84.9 %

Procedure:
A solution of tricyclohexylphophine (46 mg, 0.164 mmol) in tetrahydrofuran (2.5 mL) under nitrogen was charged with palladium (II) acetate (24.5mg, 0.109 mmol). The reaction mixture was stirred for 45 minutes, then cooled to 0° C. and charged with sodium tert-butoxide (270 mg, 2.73 mmol). After 5 minutes a solution of β-ethoxyacrylic acid ethyl ester (158 μL, 1.09 mmol) and 2-bromobenzyl phenyl sulfone (340 mg, 1.09 mmol) in tetrahydrofuran (2.5 mL) was added dropwise over 2 minutes. Upon complete addition the reaction was warmed to room temperature and then heated to 60° C. for 2 hours. The reaction was cooled to room temperature, then diluted with methyl tert-butyl ether (25 mL) and poured into aqueous potassium dihydrogen phosphate (0.25 M, 25 mL), pH=7. The aqueous layer was separated and saturated by addition of solid sodium chloride and extracted with ethyl acetate (2×50 mL). The organic layer was separated and washed twice with aqueous saturated sodium chloride (2×30 mL), dried over sodium sulfate, filtered and concentrated in vacuo affording 3-benzenesulfonyl-3H-indene-1-carboxylic acid ethyl ester as a light orange oil (304 mg, 0.925 mmol, 85%). 1H NMR (400 MHz, CDCl3) δ 7.88–7.86 (m, 1H), 7.75–7.72 (m, 1H), 7.49–7.43 (m, 3H), 7.36–7.32 (m, 2H), 7.27–7.25 (m, 3H), 5.15 (d, 1H, J=2.1), 4.27 (q, 2H, J=7.1), 1.34 (t, 3H, J=7.1); IR (ATR, neat) 1709, 1649, 1463, 1444, 1314, 1271, 1247, 1188, 1133, 1081, 1044, 773, 752, 722, 686, 575, 528.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]1[NH:27][CH2:26][CH2:25][NH:24]1>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:24]2[CH2:25][CH2:26][NH:27][C:23]2=[N:22][C:16]2[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[O:11])=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: Clc1cccc(Cl)c1N=C1NCCN1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=O)N2CCNC2=Nc2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
4.40 g (22 mmoles) of p-methylsulfonylbenzoic acid are dissolved in 70 ml of anhydrous tetrahydrofuran, 3.56 g (22 mmoles) of N,N'-carbonyldiimidazole are added and stirred at room temperature for one hour. A solution of 4.60 g (20 mmoles) of 2-(2,6-dichlorophenylimino)-imidazolidine in 50 ml of anhydrous tetrahydrofuran is added dropwise while stirring further and the mixture is allowed to stand at room temperature for 20 hours. The residue from evaporation is triturated with water, separated off, washed with water, dried and recrystallized from dimethylformamide/water (1:1). 5.15 g (62.5% of theory) of 1-(p-methylsulfonylbenzoyl)-2-(2,6-dichlorophenylimino)-imidazolidine of melting point 240°-244° C. are obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][C:26]([CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[N:25][C:24]=3[CH:34]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[N:18][N:17]=[N:16]1.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].C1(C)C=CC=CC=1>C(Cl)Cl.O>[F:8][C:9]1[CH:10]=[C:11]([C:20]2[CH:21]=[CH:22][C:23]3[O:27][C:26]([CH:28]4[CH2:29][CH2:30][N:31]([C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:33]4)=[N:25][C:24]=3[CH:34]=2)[CH:12]=[CH:13][C:14]=1[N:15]1[CH:19]=[N:18][N:17]=[N:16]1
Reactant: Fc1cc(-c2ccc3oc(C4CCNCC4)nc3c2)ccc1-n1cnnn1
Reactant: CC(C)OC(=O)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)c(F)c4)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-{5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]benzo[d]oxazol-2-yl}piperidine-1-carboxylate (120 mg, 0.26 mmol) dissolved in DCM (15 ml) and added Trifluoroacetic acid (0.5 ml). This mixture was stirred at rt for 2 h. DCM removed from the reaction mixture to obtain 5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (120 mg). 5-[3-fluoro-4-(1H-tetrazol-1-yl)phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (120 mg, 0.25 mmol) was dissolved in DCM (15 ml) and added TEA (0.27 ml, 2 mmol). This mixture stirred at rt for 30 mins and added isopropyl chloroformate in toluene (61 mg, 0.34 mmol). After 1 h, reaction mass diluted with water and extracted with DCM. Removal of DCM afforded crude. Crude was purified by combiflash using a mixture of EtOAc and Petether (35:65) as eluent to afford the titled compound (20 mg) as an off-white solid. M.P.: 187-191° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.14 (d, J 2.6, 1H), 8.02 (t, J 8.2, 1H), 7.90 (d, J 1.4, 1H), 7.63-7.55 (m, 4H), 4.95 (septet, J 6.2, 1H), 4.20 (d, J 11.2, 2H), 3.22-3.14 (m, 1H), 3.04 (t, J 11.4, 2H), 2.18 (d, J 10.8, 2H), 2.00-1.88 (m, 2H), 1.26 (d, J 6.2, 6H).