Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.I[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[N:19][C:20]=2[NH2:22])[N:15]([CH:23]([CH3:25])[CH3:24])[N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[CH:23]([N:15]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([NH2:22])=[C:21]2[C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:14]1)([CH3:25])[CH3:24]
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Temperature: 80 °C

Procedure:
A solution of 3-Methoxyphenylboronic acid (17 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA49. ESI-MS (M+H)+ m/z calcd 284.1, found 284.0.
Reaction SMILES: C[O:2][C:3](=O)/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7].[CH3:23][NH2:24]>>[CH3:23][NH:24][C:3](=[O:2])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[N:5]\[O:6][CH3:7]
Reactant: CO/N=C(\C(=O)OC)c1ccccc1Oc1cccc(C)c1
Reactant: CN
Product: CNC(=O)/C(=N\OC)c1ccccc1Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To Product (A') (286 mg), i.e. methyl-(Z)-2-[ 2-(3-tolyloxy) phenyl]-2-methoxyiminoacetate, 30% methanolic methylamine (197 mg) was added, followed by stirring at room temperature for 12 hours. Excess amine and methanol were removed from the mixture, which was subjected to silica gel column chromatography with a mixture of hexane and ethyl acetate to give 201 mg of (Z)-N-methyl-2-[2-(3 -tolyloxy) phenyl]-2-methoxyiminoacetamide (Compound No. 5 ).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)(=[O:13])=[O:12])=[O:9])=[N:4][CH:3]=1.[CH3:21][S:22](C)=O>CO>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:8](=[O:9])[NH:7][C:5]2[S:6][C:2]([S:22][CH3:21])=[CH:3][N:4]=2)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CS(C)=O
Reactant: O=C(Nc1ncc(Br)s1)NS(=O)(=O)c1cccc(Cl)c1
Solvent: CO
Product: CSc1cnc(NC(=O)NS(=O)(=O)c2cccc(Cl)c2)s1

Procedure:
Sodium methane thiolate (0.42 g, 6.0 mmol) was added to a suspension of N-[(5-bromo-1,3-thiazol-2-yl)carbamoyl]-3-chlorobenzenesulfonamide (0.60 g, 1.5 mmol) in methanol (30 ml). The mixture was heated under refluxed for 60 hours and concentrated under reduced pressure. A part of the crude (80 mg) was dissolved in acetonitrile-water and acidified using acetic acid. The precipitate formed was redissolved in DMSO and purified by preparative RP-HPLC: 14 mg lyophilisate, MS: m/e 362.1 (MH−).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([C:33]1[N:34]=[N:35][N:36]([CH3:38])[N:37]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[C:10]2[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:26]([CH3:28])=[CH:27][C:9]1=2.[N-:48]=[N+:49]=[N-:50].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:43][C:42]([F:45])([F:44])[C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([C:2]([F:46])([F:1])[F:47])[CH:41]=1)[CH2:6][N:7]([C:33]1[N:34]=[N:35][N:36]([CH3:38])[N:37]=1)[C@H:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]3[NH:50][N:49]=[N:48][N:21]=3)=[CH:18][CH:17]=2)[C:10]2[CH:24]=[C:25]([C:29]([F:30])([F:31])[F:32])[C:26]([CH3:28])=[CH:27][C:9]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(C#N)cc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1C(F)(F)F)N(Cc1ccc(-c3nnn[nH]3)cc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Yield: 88.9 %

Procedure:
Heat a mixture of (S)-4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-benzonitrile (Example 192) (0.13 g, 0.19 mmol), sodium azide (0.04 g, 0.60 mmol) and triethylamine hydrochloride (0.08 g, 0.60 mmol) in anhydrous toluene (5 mL) at 110° C. under nitrogen for 20 h. Dilute the cooled mixture with ethyl acetate (50 mL) and wash with aqueous 0.1N HCl (10 mL) and brine (10 mL). Dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with MeOH/EtOAc (0-20%), to provide the title compound (0.12 g, 82%). MS (ES+): 711 (M+H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1)(=[O:25])[CH3:24]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4[C@@H]5C[C@@H]5C(=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
A solution of 95 g of 3β-hydroxy-15β,16β-methylene-5-androsten-17-one in 190 ml of pyridine was combined with 95 ml of acetic anhydride and stirred for 1.5 hours at 95° C. The precipitate obtained after pouring the mixture into ice water was filtered off, washed thoroughly with water, and dried, thus obtaining 107 g of 3β-acetoxy-15β,16β-methylene-5-androsten-17-one as a crude product. A sample extracted by boiling with diisopropyl ether melted at 140.5°-141° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]([CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35])[Si](C(C)(C)C)(C)C.II.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:15][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([C:30]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:28][C:27]=1[CH3:35]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70° C. for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (444 mg, 39%) as a white solid. Selected data: 229-231° C.
Reaction SMILES: [N:1]1([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21]Cl)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([CH2:20][CH2:21][NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: Nc1ccccc1N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNc2ccccc2N2CCCCC2)cc1
Temperature: 100 °C

Procedure:
To 1 g of 2-piperidinoaniline in 10 mL of DMF are added 1.72 mL of 4-methoxyphenethyl chloride (2 equivalents) and 2.35 g of potassium carbonate (3 equivalents). The whole is heated to 100° C. for 60 hrs and then poured on ice and extracted with ethyl acetate. The organic phase washed with a saturated solution of sodium chloride is dried on magnesium sulfate, filtered and evaporated under reduced pressure. With several silica gel chromatographies of the residue (petroleum ether, petroleum ether/ethyl acetate: 98/2), 255 mg of the desired product were able to be isolated.
Reaction SMILES: [C:1]1([C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24](=O)[CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([NH2:46])=[S:45]>>[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]1[S:45][C:23]2[CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:13][CH:14]=3)=[O:19])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]=2[N:46]=1
Reactant: NC(=S)Cc1ccccn1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: Cl
Product: O=C(Nc1ccc(C(=O)N2CCc3sc(Cc4ccccn4)nc3-c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 58.3 %

Procedure:
Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide and 370 mg of 2-pyridylthioacetamide hydrochloride, the procedure of Example 5 was repeated, and the resulting free base was recrystallized from chloroform-diethyl ether to obtain 300 mg of 4'-[[2-(2-pyridylmethyl)-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([O:24]CC)=O.Cl.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37](Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:37]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)[C:22](=[O:24])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:1])[F:27])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: ClC(=Nc1ccccn1)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Agent: Cl
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccccn3)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1, from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)2,6-dimethyl-3,5-pyridine dicarboxylate and N-(2-pyridyl)-benzimidoyl chloride HCl (2.5 g, 9.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[CH3:17])([O-:3])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>O>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:18](=[O:20])[CH3:19])[CH:8]2[CH3:17])([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1Nc2ccccc2-c2c([N+](=O)[O-])cnn21
Solvent: O
Product: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1C
Yield: 83 %

Procedure:
22.9 g (0.1 mole) of 1-nitro-5-methyl-5,6-dihydropyrazolo[1,5-c]quinazoline is boiled with 120 ml of acetic anhydride for 1 hour, then the solution obtained is poured into water. The product that solidifies is filtered off, washed with water and dried. Thus, 25.0 g (83%) of 1-nitro-5-methyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained. M.p.: 149°-150° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.S(=O)(=O)(O)O>CCOCC>[CH2:1]([O:8][CH2:9][C:10]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)([CH2:11][OH:12])[CH2:16][OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(COCc1ccccc1)(C(=O)OCC)C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCC(CO)(COCc1ccccc1)C1CCCCC1
Temperature: 25 °C

Procedure:
Diethyl 2-benzyloxymethyl-2-cyclohexylmalonate (2 g.) was added to a suspension of lithium aluminium hydride (0.63 g.) in dry ether (30 ml), at 0° under nitrogen. The mixture was stirred at room temperature for twelve hours. Water (5 ml) was added carefully and the mixture was stirred for ten minutes. 10% sulphuric acid solution (10 ml) was added and the mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with 1:1 ether:hexane. 2-Benzyloxymethyl-2-cyclohexylpropan-1,3-diol was obtained as a colourless oil (1.0 g.).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([CH3:18])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11]2)=[CH2:7])CCC.C1C(=O)N([Br:26])C(=O)C1.Br>O.C1COCC1>[Br:26][CH2:5][C:6]([C:8]1[C:9]([CH3:18])=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[O:12][CH2:11]2)=[O:7]
Reactant: C=C(OCCCC)c1ccc2c(c1C)COC2=O
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)CBr)ccc2c1COC2=O
Temperature: 19 °C
Reaction time: 1 h

Procedure:
To a 1 L 3-neck flask equipped with overhead stirrer was added crude 5-(1-butoxy-vinyl)-4-methyl-3H-isobenzofuran-1-one (55.8 g) and THF (315 mL). The solution was cooled to <5° C. after which water (79 mL) was added and the solution was maintained at <5° C. NBS (41.6 g) was then added portionwise while maintaining Tmax=19° C. The solution was then warmed to RT for 30 minutes. HBr (48%, 0.241 mL) was added and the reaction was aged at RT for approximately 1 h after which 236 mL water was then added to the batch. A water bath is used to maintain temp at 20° C. Another 315 mL of water was added (solvent composition 1:2 THF:water) and the slurry was cooled to 15° C. The resulting solids were filtered and washed with cold 1:2 THF:water (15° C.): 150 mL displacement wash followed by 100 mL slurry wash. The solids were dried under vacuum at RT to provide 5-(2-bromo-acetyl)-4-methyl-3H-isobenzofuran-1-one.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:4]=1[Cl:13].[P:14](OCC)([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15]>>[Cl:13][C:4]1[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]([F:9])=[CH:8][C:3]=1[CH2:2][P:14](=[O:15])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: O=[N+]([O-])c1cc(Cl)c(CBr)cc1F
Reactant: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(Cc1cc(F)c([N+](=O)[O-])cc1Cl)OCC

Procedure:
1-(Bromomethyl)-2-chloro-5-fluoro-4-nitrobenzene (6.7 g, 18.62 mmol) and triethyl phosphate (5.64 mL) were heated in an oil bath for 3 hours at 140° C. The reaction mixture was concentrated and chromatographed on silica eluting with dichloromethane/methanol (1:0-1%) to give the title compound (4.06 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][CH:37]=[O:38])[CH2:31][CH2:30]1.[CH3:39][Mg]Br.O1CCCC1>O1CCCC1.[Cl-].[NH4+]>[OH:38][CH:37]([CH3:39])[CH2:36][O:35][C@H:32]1[CH2:31][CH2:30][C@H:29]([N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][CH:10]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)[CH2:34][CH2:33]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC=O)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4′-({5-oxo-4-[trans-4-(2-oxoethoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (841 mg) in tetrahydrofuran (15 mL) was added 1 M methylmagnesium bromide-tetrahydrofuran solution (2.2 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=70/30→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (387 mg, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(Cl)Cl.CO>N1C=CC=CC=1>[CH3:18][N:19]([CH3:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([C:9]3[N:10]=[C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]4[CH:8]=3)=[CH:12][CH:13]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccc(N(C)C)cc4)cc3)cn2c1
Yield: 54.2 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (70 mg, 0.314 mmol) and 4-dimethylaminobenzoyl chloride (58 mg, 0.314 mmol) in dry pyridine (5 ml) to give the title compound (63 mg, 54%) as a pale yellow solid after work-up and flash chromatography (20:1 DCM/MeOH).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[C:22]2[C:17](=[CH:18][C:19]([S:23]([O:26][C:27]3[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=3[F:37])(=[O:25])=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.[O:38]1[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.C(OCC)(=O)C.O>[O:38]1[CH2:43][CH2:42][CH:41]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[C:22]3[C:17](=[CH:18][C:19]([S:23]([O:26][C:27]4[C:28]([F:37])=[C:29]([F:36])[C:30]([F:35])=[C:31]([F:34])[C:32]=4[F:33])(=[O:24])=[O:25])=[CH:20][CH:21]=3)[CH:16]=[CH:15][N:14]=2)[CH2:40][CH2:39]1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)nccc2c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3C3CCOCC3)nccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Perfluorophenyl 1-(pyrrolidin-2-yl)isoquinoline-6-sulfonate 2,2,2-trifluoroacetate (Intermediate ZZZ; 0.100 g, 0.179 mmol) and tetrahydro-4h-pyran-4-one (0.025 ml, 0.269 mmol) were dissolved in DCM (1.791 ml). Sodium triacetoxyborohydride (0.114 g, 0.537 mmol) and acetic acid (0.015 ml, 0.269 mmol) were added and the reaction was stirred for one hour at room temperature. Water was added followed by ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to afford perfluorophenyl 1-(1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-2-yl)isoquinoline-6-sulfonate as an oily blue solid. m/z (ESI) 529.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12](Cl)(=O)=O)=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(O)C>O.Cl.[Zn]>[Cl:1][C:2]1[C:3]([SH:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)c(S(=O)(=O)Cl)cc2o1
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(S)cc2o1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 102.4 %

Procedure:
Zinc dust (14.4 g, 0.22 mol) was added to a solution of mercuric chloride (2.86 g, 10.6 mmol) in water (42 mL) and concentrated hydrochloric acid (1.7 mL). The mixture was stirred for 15 min and the supernatant poured off. The residue was washed with water (2×15 mL), ethanol (2×15 mL) and diethyl ether (2×15 mL). 5-chloro-6-chlorosulfonyl-3H-benzooxazol-2-one (12.3 g, 46 mmol) and ethanol (70 mL) were added to the residue and the mixture placed in an ice-bath. Concentrated hydrochloric acid (36 mL) was added via addition funnel over 15 min and the resulting mixture stirred at reflux for 18 hours. The cooled reaction mixture was poured into ice-cold water (300 mL) and stirred for 20 min. The precipitate was collected to give 9.5 g of a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[OH:11])[CH:5]=[CH:4][CH:3]=1.Br[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)CC)C.O>CN(C)C(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][CH:10]([CH:12]2[CH2:13][CH2:14][N:15]([C:19]3[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:16][CH2:17]2)[OH:11])[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Br
Reactant: Cc1cccc(C#CC(O)C2CCNCC2)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(C#CC(O)C2CCN(c3ncccc3[N+](=O)[O-])CC2)n1
Yield: 74.2 %

Procedure:
A well homogenised mixture of Compound 237a (200 mg, 0.86 mmol), 2-bromo-3-nitropyridine (194 mg, 0.95 mmol) and triethylamine (249 μL, 1.74 mmol) in N,N-dimethylacetamide (15 mL) was stirred at r.t. for 4 h. Afterwards, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with Petroleum Ether-EtOAc 7:3, affording the title product (225 mg) as a yellow oil.
Reaction SMILES: O.C(O)C.C(O)(=O)C.[Cl:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[C:12]([N+:18]([O-])=O)[CH:11]=1.CC(C)=O>[Fe].CCCCCC.C(OCC)(=O)C>[NH2:18][C:12]1[CH:11]=[C:10]([Cl:9])[C:15]([CH3:16])=[CH:14][C:13]=1[OH:17]
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Cc1cc(O)c(N)cc1Cl
Yield: 41.9 %

Procedure:
To 15 ml of a solvent mixture of water-ethanol (1:1 (v:v)), there was added 0.5 ml of glacial acetic acid and heated under reflux. To the obtained solution, there were added 0.86 g of iron powder and 0.80 g (4.3 mmol) of 4-chloro-5-methyl-2-nitrophenol and the mixture was heated under reflux for additional 20 minutes. After cooling and adding 30 ml of acetone, the iron powder was filtered and washed with 50 ml of acetone. The filtrate was combined with the washing liquor and the solvent was distilled off therefrom under reduced pressure to thereby give a brown solid. The obtained product was subjected to silica gel column chromatography (Si60 manufactured by Merck; 230-400 mesh; 200 g; eluent: hexane-ethyl acetate (2:1 (v:v)). The solvent was distilled off from the 1,100-2,000 ml fraction and thus 0.29 g (1.8 mmol) of 2-amino-4-chloro-5-methylphenol was obtained as yellow crystals. The yield was 43%.