Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1)#[CH:2].I[C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[C:14]([OH:16])=[O:15]>>[F:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:11]2[CH:12]=[C:13]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=2[O:20][CH3:21])[C:14]([OH:16])=[O:15])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc(C(=O)O)cc(I)c1OC
Reactant: C#Cc1cccc(F)c1
Product: COc1cc(C(=O)O)cc(C#Cc2cccc(F)c2)c1OC

Procedure:
3-(3-Fluorophenylethynyl)-4,5-dimethoxybenzoic acid was prepared by coupling 1-ethynyl-3-fluorobenzene with 3-iodo-4,5-dimethoxybenzoic acid Method R. The crude product was purified via flash column chromatography on silica gel (5% MeOH in CH2Cl2 as an eluent) to give 3-(3-fluorophenylethynyl)-4,5-dimethoxybenzoic acid in 95% yield. ESMS: m/z 299.3 [M−H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[Br:15][C:16]1[CH:17]=[C:18]([C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[N:23]S(C(C)(C)C)=O)[CH:19]=[CH:20][CH:21]=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[C:18]([C:22]2([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[C:30]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]([NH2:37])=[N:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1ccccc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a −78° C. solution of 4-bromoanisole (0.45 mL, 3.6 mmol) in tetrahydrofuran (15 mL) was n-butyllithium (2.5 M in hexane, 1.3 mL, 3.3 mmol) added, after 0.5 h a solution of N-[(3-bromophenyl)(2-cyanophenyl)methylene]-2-methylpropane-2-sulfinamide (Scheme #5, N) (1.2 g, 3.0 mmol) in tetrahydrofuran (5 mL) was added. The reaction mixture was stirred at −78° C. for 3 h and then quenched by addition of water. Ethyl acetate was added and the mixture was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was dissolved in methanol (25 mL) and treated with hydrochloric acid (2 M in diethyl ether, 3.0 mL, 6.0 mml) over night. The reaction mixture was concentrated and then partitioned between aqueous saturated sodium bicarbonate and chloroform, the organic phase was dried over magnesium sulfate and concentrated. Purification by column chromatography using a gradient of methanol in dichloromethane gave the title compound (0.70 g, 59%). 1H NMR (CDCl3) δ 7.57-7.48 (m, 3 H), 7.47-7.41 (m, 1 H), 7.39-7.32 (m, 2 H), 7.32-7.28 (m, 1 H), 7.26-7.20 (m, 2 H), 7.10 (t, J=7.83 Hz, 1 H), 6.83-6.77 (m, 2 H), 5.86 (br s, 2 H), 3.75 (s, 3 H); MS (AP) m/z 393, 395 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Cl.C(N(CC)CC)C.[N-:20]=[N+:21]=[N-:22].[Na+]>COCCOC>[NH:20]1[C:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH:7]=[CH:6]3)=[N:2][N:22]=[N:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: c1cc2cc(-c3nnn[nH]3)ccc2[nH]1

Procedure:
A mixture of 5-cyano-1H-indole (88 g), triethylamine hydrochloride (225 g), and sodium azide (150 g) was heated in 1,2-dimethoxyethane (DME) at reflux temperature for 48 hours. The solvent was evaporated in vaciio and the residue was dissolved in ethyl acetate (500 mL) and water (500 mL). pH was adjusted to 10 by addition of concentrated aqueous NaOH solution. The aqueous phase was separated and pH was adjusted to 4 by addition of acetic acid. The precipitated crystalline title compound 1a was filtered off and subsequently dried in vacuo. Yield 82 g, mp 205° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:42])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:32]=[C:31]([CH2:33][O:34]C3CCCCO3)[O:30][N:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:32]=[C:31]([CH2:33][OH:34])[O:30][N:29]=4)[CH:23]=3)[CH2:20][C:19](=[O:42])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)on3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(CO)on3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-dimethylamino-2-(3-oxo-3-{3-(5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert.-butyl ester (Example M43) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (113 mg).
Reaction SMILES: BrC1C=C(N[C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:14])C=C(Br)C=1OCC.C(Cl)CCl.[CH2:29]([O:31][C:32]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[C:43]([F:46])([F:45])[F:44])[CH3:30]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:29]([O:31][C:32]1[C:33]([C:43]([F:44])([F:45])[F:46])=[CH:34][C:35]([NH:36][C:13]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[O:14])=[CH:37][C:38]=1[C:39]([F:40])([F:41])[F:42])[CH3:30]
Reactant: CCOc1c(C(F)(F)F)cc(N)cc1C(F)(F)F
Reactant: CCOc1c(Br)cc(NC(=O)c2ccc(C(=O)OC)cc2)cc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1c(C(F)(F)F)cc(NC(=O)c2ccc(C(=O)OC)cc2)cc1C(F)(F)F
Yield: 26.1 %

Procedure:
4-(Methoxycarbonyl)benzoic acid (4) (246 mg, 1.37 mmol) was dissolved in DCM (15 mL) and treated with EDC (654 mg, 3.41 mmol) and DMAP (33 mg, 273 μmol). The resultant mixture was stirred at RT for 15 min. 4-Ethoxy-3,5-bis(trifluoromethyl)aniline (3) (360 mg, 1.32 mmol) was added and the resultant mixture was stirred at RT for 20 h. The mixture was diluted with EtOAc and washed three times with 1 M HCl and then three times with NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by silica gel chromatography (10% EtAOc in isohexane) to afford methyl 4-(4-ethoxy-3,5-bis(trifluoromethyl)phenylcarbamoyl)benzoate (5) (150 mg, 28%): m/z 436 [M+H]+ (ES+).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:22]1([CH2:28][CH2:29][OH:30])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([N:25]4[CH2:26][CH2:27][N:22]([CH2:28][CH2:29][OH:30])[CH2:23][CH2:24]4)=[O:18])=[CH:20][CH:21]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: OCCN1CCNCC1
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)N1CCN(CCO)CC1
Yield: 90.2 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)phenoxy)acetic acid (0.15 g, 0.52 mmol) and 2-(piperazin-1-yl)ethanol (0.068 g, 0.52 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)phenoxy)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethanone as a white solid (0.187 g, 90.3% yield).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:23]=[CH:24][C:10]=13)[CH2:2]2.Cl[C:30](Cl)([O:32][C:33](=O)[O:34]C(Cl)(Cl)Cl)Cl.CO.C(N1C2=NC(C3C=CC(N=C=O)=CC=3)=NC(N3CC4OC(CC4)C3)=C2C=N1)(C)(C)C>ClCCl.O1CCCC1>[CH3:30][O:32][C:33](=[O:34])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Agent: CC(C)(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N=C=O)cc3)nc21
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C(C)(C)C)c3n2)cc1

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (65 mg, 0.17 mmol) in a mixture of dichloromethane (2 mL) and tetrahydrofuran (2 mL) was treated with triphosgene (26 mg, 0.09 mmol) as a solution in dichloromethane (1 mL). After the passage of 10 minutes, the appropriate nucleophile—in the case, methanol (excess)—was added to the 3-(1-tert-butyl-6-(4-isocyanatophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide methyl{4-[1-tert-butyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate. MS (ES+): 437.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([C:17]4[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=4[O:27][CH:28]([CH3:30])[CH3:29])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>ClCCl>[F:1][C:2]1[C:10]2[N:9]([S:32]([CH3:31])(=[O:34])=[O:33])[C:8]3[CH2:11][CH2:12][N:13]([C:15]([C:17]4[CH:22]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:20]=[CH:19][C:18]=4[O:27][CH:28]([CH3:30])[CH3:29])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2[nH]c3c(F)cccc3c2C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(c3cccc(F)c3n2S(C)(=O)=O)C1
Reaction time: 8 h

Procedure:
A suspension of 200 mg (6-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 17) in 5 ml dichloromethane was treated with 106 mg methane sulfonyl chloride, followed by 118 mg triethylamine. The reaction mixture was stirred overnight. Concentration and chromatography (silica gel; ethyl acetate) yielded the title compound as a slightly yellowish solid (17 mg; 7%). MS (m/e): 509.0 (M+CH3COO).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([OH:16])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([O:39][CH2:40][C:41]([C:43]1[CH:44]=[CH:45][C:46]2[C:50]3[CH:51]=[CH:52][C:53]([C:55](=[O:58])[CH2:56]Br)=[CH:54][C:49]=3[O:48][C:47]=2[CH:59]=1)=[O:42])=[O:38])=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(#N)C.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([O:16][CH2:56][C:55]([C:53]2[CH:52]=[CH:51][C:50]3[C:46]4[CH:45]=[CH:44][C:43]([C:41](=[O:42])[CH2:40][O:39][C:37]([CH:33]5[CH2:34][CH2:35][CH2:36][N:32]5[C:30]([O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:31])=[O:38])=[CH:59][C:47]=4[O:48][C:49]=3[CH:54]=2)=[O:58])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)oc1cc(C(=O)CBr)ccc12
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)oc1cc(C(=O)COC(=O)C3C4CCC(C4)N3C(=O)OC(C)(C)C)ccc12
Reaction time: 10 h
Yield: 93.2 %

Procedure:
To the solution of 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (155 mg, 0.64 mmol) and triethylamine (77 μl, 0.55 mmol) in acetonitrile (3 ml) was added a solution of Pyrrolidine-1,2-dicarboxylic acid 2-{2-[7-(2-bromo-acetyl)-dibenzofuran-3-yl]-2-oxo-ethyl}ester 1-tert-butyl ester (200 mg, 0.37 mmol) in DMF (6 ml). The mixture was stirred for 10 hours, and the solvent was evaporated. The mixture was diluted with EtOAc, and washed with water and brine, and was dried with sodium sulfate. Concentration gave 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-dibenzofuran-3-yl}-2-oxo-ethyl) ester 2-tert-butyl ester (243 mg). m/z: 703.3 (M−1), 727.2 (M+Na)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:15]1([C:2]2[N:7]=[C:6]3[O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:5]3=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(n1)oc1ccccc12
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc3c(n2)oc2ccccc23)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
2-chlorobenzofuro[2,3-b]pyridine (1.33 g, 6.53 mmol), phenylboronic acid (1.19 g, 9.80 mmol), potassium phosphate (4.51 g, 19.59 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.214 g, 0.522 mmol) and Pd2(bda)3 (0.119 g, 0.13 mmol) were to toluene (40 mL) and water (4 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was extracted with ethylacetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethylacetate and hexanes as the eluent. The solvent was removed to give 1.45 g of title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33]O)[CH2:29][CH2:28]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([O:1][CH2:33][CH:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)[CH:3]=2)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: OCC1CCOCC1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCC3CCOCC3)c2[nH]1
Temperature: 50 °C
Reaction time: 13 h
Yield: 128.8 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (400 mg), tetrahydro-2H-pyran-4-ylmethanol (250 mg), 1,1′-(azodicarbonyl)dipiperidine (540 mg), tributylphosphine (0.5 mL) and tetrahydrofuran (10 mL) was stirred at 50° C. for 13 hr. The reaction solution was allowed to cool to room temperature, and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=3:97-45:55, volume ratio) to give the crude title compound (650 mg) as an orange oil. MS 474 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17]C3CCCCO3)=[CH:14][CH:15]=2)[C:10]([C:24](=[O:26])[CH3:25])=[C:9]1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([C:24](=[O:26])[CH3:25])=[C:9]1[CH:27]([CH3:29])[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(OC3CCCCO3)cc12
Agent: Cl
Solvent: CO
Product: CC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccc(O)cc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
General Procedure D. To a solution of 1-(1-benzyl-2-isopropyl-5-(tetrahydropyran-2-yloxy)-1H-indol-3-yl)ethanone (Compound 14, 60 mg, 0.16 mmol) in MeOH was added aq. HCl (1 mL), and the solution was stirred for 5 min. at room temperature. The reaction was quenched by adding 5% aqueous NaHCO3 (2 mL), and the product was extracted with EtOAc (30 mL). The organic layer was separated, and washed with water, and brine, and dried (Na2SO4), and the solvent was removed under vacuum. Flash chromatography on silica gel with 20% EtOAc in hexane gave 1-(1-benzyl-5-hydroxy-2-isopropyl-1H-indol-3-yl)ethanone (Compound 17) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[C:31]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.C(Cl)Cl>[C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:20][CH:19]=1)#[CH:31]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of compound 5f (0.30 g, 0.73 mmol, Example 5) in MeOH (5 mL) was added K2CO3 (0.30 g, 2.2 mmol) and a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (0.18 g, 0.96 mmol) in MeOH (2 mL). The reaction mixture was stirred at rt for 2 days, and concentrated under reduced pressure. The residue obtained was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3×10 mL). The combined organic extracts were washed with brine, and dried over MgSO4. The mixture was filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (20-60% EtOAc/heptane) to give the compound 17a as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C23H24N4O3: 405.2 (M+H). found: 405.2.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=O)[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:22].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([NH2:29])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:22]
Reactant: CC(=O)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 1-[4-chloro-7-(3,5-difluorophenyl)-1-methyl-1H-indazol-6-yl]ethanone (0.438 g, 1.36 mmol), ammonium acetate (1.05 g, 13.6 mmol) and sodium cyanoborohydride (0.172 g, 2.73 mmol) in methanol (5 mL) and acetonitrile (5 mL) was heated at 65° C. overnight, in a sealed tube. The mixture was then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness to give the desired product. LCMS calculated for C16H12ClF2N2 (M−NH2)+: m/z=305.1; Found: 305.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(O)(=O)C>S(=O)(=O)(O)O>[C:12]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=1)[OH:11])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)OC(=O)c1cc(Cl)ccc1O
Temperature: 70 °C
Yield: 76 %

Procedure:
5-Chlorosalicylic acid (17.3 g, 100 mmol) and three drops of concentrated sulfuric acid (98%) were added to a solution of acetic anhydride (14 g, 137 mmol) and glacial acetic acid (16.4 g, 274 mmol) with stirring. The reaction mixture was slowly heated to 70° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature and was gradually added to ice water (500 mL) to precipitate the acetylated product. These solids were collected and washed with water. The two batches of product were combined and recrystallized in ethyl acetate. The pure crystals were collected via vacuum filtration to give 16.3 g of O-acetyl-5-chlorosalicylic acid (76 mmol, 76% yield).
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][CH2:6][C:7]([CH:9]=[CH2:10])=[CH2:8])[CH3:3].[CH:12]([O:14]CCCC)=[CH2:13].C([O-])(=O)C.[Na+]>>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7]([CH:9]=[CH2:10])=[CH2:8])[CH2:3][CH2:13][CH:12]=[O:14]
Reactant: C=COCCCC
Reactant: C=CC(=C)CCCC(C)(C)O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CC(=C)CCC=C(C)CCC=O
Yield: 75 %

Procedure:
A mixture of 50 g. of sec.-myrcenol (prepared according to the method described in paragraph b) above), 300 g. of n-butyl vinyl ether, 1 g. of mercuric acetate and 10 g. of sodium acetate were refluxed for 40 hours (120°) under nitrogen. During this heating period 1 g. of additional mercuric acetate was added every 6 hours. The laboratory vessel was connected to a downward directed condenser, and the excess of n-butyl vinyl ether was distilled under ordinary pressure. The residue was distilled under vacuum. A yield of 75% of 4-methyl-8-vinyl-4,8-nonadienal that contained approximately 15% of unreacted alcohol was obtained. This alcohol could be recovered when the above C12 aldehyde was converted to β-sinensal.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=1.Cl.Cl.[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:14])[CH3:13])[CH3:10])=[CH:5][CH:4]=3)[CH2:26][CH2:25]2)=[CH:22][CH:23]=1
Reactant: CC(=O)N[C@H](C)c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CC(=O)N[C@H](C)c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using (R)-N-(1-(4-chloromethylphenyl)ethyl)acetamide instead of N-(4-chloromethylphenylmethyl)acetamide and 1-(4-fluorophenyl)piperazine dihydrochloride instead of phenylpiperazine, the title compound was obtained as white crystals, m.p.=114-115° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:9]
Reactant: C=C(C)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=CBr)c1ccccc1

Procedure:
100 g of N-bromosuccinimide are added to the mixture of 250 ml of α-methylstyrene and 40 ml of carbon tetrachloride. The resulting mixture is heated to reflux for 5 min. and cooled in an ice-water bath. Filtration and concentration give the desired compound, 1-bromo-2-phenylpropene, and an isomer thereof (65:35).
Reaction SMILES: [OH:1][C@H:2]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][NH:4][C:5]([C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=2)[O:8]1)=O.CO.Cl.[OH-].[Na+]>C1COCC1.O.C(OCC)(=O)C>[N+:17]([C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([CH2:5][NH:4][CH2:3][C@@H:2]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[OH:1])[CH2:16][CH2:15]2)([O-:19])=[O:18]
Reactant: O=C(NC[C@H](O)c1cccnc1)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)CC[C@H](CNC[C@H](O)c1cccnc1)O2
Yield: 65.8 %

Procedure:
(2R)-N-[(2R)-2-Hydroxy-2-(3-pyridinyl)ethyl]-6-nitro-3,4-dihydro-2H-chromene-2-carboxamide (Example 169, 1.0 g, 3 mmol) was dissolved in 15 mL of THF and borane-dimethylsulfide complex (1.4 mL, 12.6 mmol) was added dropwise. The reaction was refluxed for one hour after which TLC showed no remaining starting material. Methanol (0.5 mL) was then added dropwise followed by 6N HCl (0.5 mL) and the reaction was refluxed an additional 1.5 hours. The solution was then cooled and diluted with water and ethyl acetate, and adjusted to about pH 9 with 1N NaOH. The organic layer was dried and evaporated to afford the product (650 mg) as a yellow solid. 1H NMR (DMSO-d6, δ): 8.6 (s, 1H), δ 8.5 (d, 1H), δ 8.1 (s, 1H), δ 8.0 (d, 1H), δ 7.8 (d, 1H), δ 7.4 (m, 1H), δ 7.0 (d, 1H), δ 5.6 (s, 1H), δ 4.8 (m, 1H), δ 4.3 (m, 1H), δ 3.2 (s, 1H), δ 2.9 (m, 2H), δ 2.8 (m, 2H), δ 2.1 (m, 1H), δ 1.8 (m, 1H); LC/MS: m/z 329, MH+ 330