Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([O:13][CH3:17])=[O:12]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(CC(=O)O)c(F)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OC)cc1F
Reaction time: 0.25 h

Procedure:
To a solution of (2-fluoro-4-methoxyphenyl)acetic acid (500 mg, 2.72 mmol) in toluene (20 mL) was added MeOH (3 mL) and TMS diazomethane (2.04 mL of a 2M solution in hexanes, 4.08 mmol). After 15 min, the reaction was quenched by the addition of HOAc (250 μL). The reaction was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 (2×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and concentrated. Purification of the residue by flash chromatography (0 to 25% EtOAc/hexanes) afforded methyl (2-fluoro-4-methoxyphenyl)acetate. 1H NMR (500 MHz, CDCl3): δ 7.15 (t, J=8.6 Hz, 1H), 6.62-6.68 (m, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.60 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([CH2:21][OH:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:23]([C:26]2[CH:27]=[N:28][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH:38]1([CH2:41]Br)[CH2:40][CH2:39]1>>[CH:38]1([CH2:41][O:22][CH2:21][C@@:19]23[CH2:18][N:17]([S:23]([C:26]4[CH:27]=[N:28][C:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:30][CH:31]=4)(=[O:24])=[O:25])[CH2:16][CH2:15][C:14]2=[CH:13][C:12]2[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[CH:10][C:11]=2[CH2:20]3)[CH2:40][CH2:39]1
Reactant: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Reactant: BrCC1CC1
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(COCC2CC2)C1

Procedure:
The title compound was prepared by the method of Preparation 25b using [(R)-1-(4-fluorophenyl)-6-[[6-(4-morpholinyl)-3-pyridinyl]sulfonyl]-1,4,7,8-tetrahydro-1,2,6-triazacyclopenta[b]naphthalen-4a-yl]methanol and cyclopropylmethyl bromide. 1H NMR (400 MHz, CHCl3-d): δ 8.54 (d, 1H), 7.80 (dd, 1H), 7.51-7.39 (m, 3H), 7.14 (t, 2H), 6.62 (d, 1H), 4.17 (dd, 1H), 3.80 (t, 4H), 3.65 (t, 4H), 3.45 (d, 1H), 3.30 (dd, 2H), 3.27-3.14 (m, 2H), 2.75-2.65 (m, 1H), 2.43-2.33 (m, 2H), 2.21-2.10 (m, 1H), 2.10 (d, 1H), 1.12-1.01 (m, 1H), 0.49 (dd, 2H), 0.26-0.15 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([NH:70][CH2:71][C:72]([O:74][CH2:75][CH3:76])=[O:73])=[CH:66][CH:65]=1>>[CH2:75]([O:74][C:72](=[O:73])[CH2:71][NH:70][C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([C@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[CH:65][CH:66]=1)[CH3:76]
Reactant: CCOC(=O)CNc1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ccc(NC(=O)[C@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 29.7 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (89 mg, 0.690 mmol), diphenylphosphinic chloride (Alfa Aesar, 106 mg, 0.446 mmol), then reacted with ethyl 2-(4-aminophenylamino)acetate (35 mg, 0.181 mmol) to give rac-(4-{[(2′S,3′R,4′S,5′S)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-phenylamino)-acetic acid ethyl ester (33 mg, 29%). MS (ES+) m/z [(M+H)+]: 641
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([CH3:30])=[C:19]([C:31]([OH:33])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:20]([CH3:30])=[C:19]([C:31]([NH:34][C@@H:35]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]4)=[O:33])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Product: Cc1c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncnc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c2) and commercially available tert-butyl (R)-3-amino-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH:8]1([Mg]Cl)[CH2:12][CH2:11][CH2:10][CH2:9]1.[Cl-].[NH4+]>ClCCl.O=[Mn]=O>[CH:8]1([CH:3]2[CH2:4][O:5][CH2:6][CH2:7][N:2]2[OH:1])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cl[Mg]C1CCCC1
Reactant: ON1CCOCC1
Agent: O=[Mn]=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: ON1CCOCC1C1CCCC1
Reaction time: 1 h
Yield: 29 %

Procedure:
Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclopentylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 70% diethyl ether in hexanes to give the title compound (0.246 g, 29%) as a white crystalline solid.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:15].C(N(CC)CC)C>C(OCC)C>[CH2:17]([O:16][C:14]([O:12][C:10]([CH3:11])=[CH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(=O)OC(C)=CC(=O)c1ccccc1
Yield: 80.6 %

Procedure:
The preparation is carried out as described in Example 1, using 17.8 g (0.11 mole) of benzoylacetone, 30.5 g (0.1 mole) of n-hexadecyl chloroformate and 100 ml of diethyl ether as well as 11 g (0.11 mole) of triethylamine. The crude product (34.7 g) obtained is recrystallised from a mixture of 85 ml of isopropanol and 10 ml of water. The white crystals melt at 31° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1)=O>>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[N:12]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=3)[S:13][CH:24]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccc(Br)cc1
Product: O=C(O)c1cc(-c2nc(-c3ccc(Br)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 68 %

Procedure:
4-[4-(4-Bromo-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (205 mg, 68%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2,4′-dibromoacetophenone (available from Alfa Aesar) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.34 (s, J=8.3, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.14 (dd, J=8.1, 1.1 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.62-7.81 (m, 4H), 7.40-7.47 (m, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:16][CH2:17]1
Reactant: Clc1cnccn1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)OCC(CN1CCN(c3cnccn3)CC1)O2
Temperature: 100 °C
Yield: 27.2 %

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)piperazine (2.35 g, 10 mmole), 2-chloropyrazine (1.15 g, 10 mmole) and diisopropylethylamine (1.3 g, 10 mmole) were combined in 100 ml of 1-methyl-2-pyrrolidinone and heated under N2 at 100° C. for 24 hours. Upon cooling, the solvent was removed in vacuum and the residue filtered through 75 g of silica gel using chloroform as the eluent. The product-containing fractions were combined, the solvent evaporated and the residue was crystallized from methanol with addition of 4N isopropanolic HCl. A second recrystallization from methanol gave 850 mg of title compound, as the dihydrochloride salt, m.p. 248°-253° C.(d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42][NH2:43])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42][NH:43][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(-c2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[4-(2-Pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-benzoic acid (Example 41 before reverse phase chromatography, 0.08 g, 0.185 mmol), (2-aminoethyl)-carbamic acid tert-butyl ester (0.036 g, 0.2 mmol), N—N-Diisopropylethylamine (0.08 mL, 0.46 mmol) and HBTU (0.076 g, 0.2 mmol) are mixed in 10 mL of DMF and stirred at RT for 8 h under nitrogen. The crude mixture is diluted with EtOAc (30 mL) and extracted with saturated NaHCO3. The organic phase is separated and washed with saturated brine, dried (Na2SO4), filtered, evaporated to a solid mass. The crude product is purified by MPLC on silica gel (80% EtOAc/Hexanes, 1% MeOH) to yield the title compound, 0.059 g (56%), as white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1.C1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:22])(=[O:1])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCC1CCc2ccccc2O1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 25 h
Yield: 84.5 %

Procedure:
To a stirred and cooled (0° C.) solution of 32.8 g of 3,4-dihydro-2H1-benzopyran-2-methanol in 71 ml of pyridine and 135 ml of benzene was added dropwise a solution of 41.9 g of 4-methyl-benzenesulfonyl chloride in 72.5 ml of benzene. Upon completion, stirring was continued for 25 hours. The reaction mixture was washed successively with a hydrochloric acid solution (10%), with water and with a sodium carbonate solution (10% ). The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 100%). The eluent of the desired fraction was evaporated, yielding 28.3 g of 3,4-dihydro-2H1-benzopyran-2-methanol 4-methylbenzenesulfonate (ester) as a solid residue, mp. 59.4° C. (interm. 1).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=2[CH2:16][OH:17])[CH2:3][CH2:2]1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[CH:1]1([O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:6]=2[CH:16]=[O:17])[CH2:3][CH2:2]1
Reactant: OCc1cc(OC(F)(F)F)ccc1OC1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
Sulfur trioxide pyridine complex (0.90 g, 5.7 mmol) was added to a solution of 2-cyclopropoxy-5-(trifluoromethoxy)benzenemethanol (Description 13, 393 mg, 1.6 mmol) and triethylamine, (1.54 mL, 11.1 mmol) in dimethylsulfoxide (3 mL) and the mixture was stirred at room temperature for 45 min. Further triethylamine (0.44 mL, 3.2 mmol) and sulfur trioxide pyridine complex (0.126 g, 0.8 mmol) were added and the mixture was stirred at room temperature for 30 min. The mixture was poured into aqueous citric acid (10%, 50 mL) and extracted with ethyl acetate. The combined organic fractions were washed with aqueous citric acid (10%, 3×50 mL) and water (3×50 mL), dried (Na2SO4), and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (0.326 g, 84%). 1H NMR (360 MHz, CDCl3) δ0.86 (4H, m), 3.82-3.9 (1H, m), 7.42 (2H, m), 7.62 (1H, d, J 2.5 Hz), and 10.36 (1H, s).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH:3]=[N:2]1.[CH3:13][O:14][CH2:15]Cl>CN(C=O)C>[CH3:13][O:14][CH2:15][N:1]1[CH:5]=[C:4]([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH:3]=[N:2]1
Reactant: O[C@@H]1CCCC[C@H]1c1cn[nH]c1
Reactant: COCCl
Solvent: CN(C)C=O
Product: COCn1cc([C@@H]2CCCC[C@H]2O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of the (1R,2S)-2-(1H-pyrazol-4-yl)cyclohexanol (170 mg, 1.02 mmol) prepared in Example 169b in DMF (5.0 mL), chloromethyl methyl ether (0.078 mL, 1.02 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was vacuum concentrated, and the residue was then purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (132 mg, 61%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])(=[O:6])=[O:5])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCN(CC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCN(CC)S(=O)(=O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 106.5 %

Procedure:
A 250 mL Parr shaker bottle was charged with N,N-Diethyl-4-nitro-benzenesulfonamide (617 mg, 2.39 mmol), ethyl acetate (50 mL), and 10% palladium on activated carbon (100 mg). The bottle was place on a Parr shaker apparatus and charged with hydrogen to a pressure of 52 psi. The reaction mixure was shaken for two hours, filtered through celite, and concentrated to provide 4-Amino-N,N-diethyl-benzenesulfonamide as a green solid (581 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:11])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)O)ccc1Br
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 4-bromo-3-methylbenzaldehyde (4 g, 20 mmol) in tetrahydrofuran (40 mL) was cooled to 0° C. then methylmagnesium bromide (20 mL, 1N in tetrahydrofuran) was dropped and the mixture was stirred at 0° C. to room temperature for 2 hours. Ammonium chloride aqueous (40 mL) was added and the mixture was extracted with dichloromethane (3*20 mL), dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=20:1) to give 1-(4-bromo-3-methylphenyl)ethanol as a colorless oil (4.0 g, 93%).
Reaction SMILES: [CH3:1][NH2:2].[N:3]([C:6]1[CH:7]=[C:8]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:9]=[CH:10][CH:11]=1)=[C:4]=[O:5]>O1CCCC1.C(OCC)(=O)C>[CH3:1][NH:2][C:4]([NH:3][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[CH:7]=1)=[O:5]
Reactant: CC1(C)OB(c2cccc(N=C=O)c2)OC1(C)C
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reaction time: 0.08 h

Procedure:
Methyl amine (2.0 M in THF) was added to a solution of 2-(3-isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.49 g, 2.0 mmol) and in tetrahydrofuran (6.0 mL) at 0° C. The mixture was stirred at this temperature for 5 min, then at r.t. for 2 h. The mixture was diluted with ethyl acetate, washed with water, 1N HCl aq. and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide the desired product which was directly used in next step without further purification. LCMS (M+H)+: m/z=277.1
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8](O)=O)=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([C:8]2[S:17][C:16]([NH2:18])=[N:15][N:14]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: Cc1ccc(OC(C)C(=O)O)cc1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(OC(C)c2nnc(N)s2)cc1
Temperature: 90 °C

Procedure:
A 100 milliliter flask adapted with a paddle stirrer, thermometer, addition funnel, condenser and drying tube was charged with 7.2 grams (0.040 mole) of 2-(4-methylphenoxy)propanoic acid, 3.6 grams (0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane, and heated to 90° C. the addition funnel was charged with phosphorous oxychloride (POCl3), (6.7 grams, 0.4 mole) which was slowly added for 15 minutes while maintaining the temperature within 90°-95° C. When the addition was completed, the mixture was refluxed for 60 minutes. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), and then 50 milliliters of water was added and mixture was made basic by the addition of 50 percent solution of NaOH until the pH of the solution was 10. The white precipitate was filtered off, washed with water and dried in a vacuum oven at 80° C. to 7.7 grams of tan crystals (melting point 142°-162° C.) which were recrystallized from the minimum amount of a water ethanol mixture, filtered off and dried in a vacuum oven at 80° C. to 4.8 grams of yellow crystals of 5-[1-(4-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole (melting point 178°-180° C.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[C:11]([I:12])=[C:10]([CH:13]=[O:14])[CH:9]=[C:8]1[C:15]([O:17][CH3:18])=[O:16].N1C2C(=CC=CC=2)C(CCCC[OH:35])=C1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:13]([C:10]1[CH:9]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[N:7]([CH2:6][C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([CH2:2][OH:35])[CH:4]=2)[C:11]=1[I:12])=[O:14]
Reactant: COC(=O)c1cc(C=O)c(I)n1Cc1cccc(CBr)c1
Reactant: OCCCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=O)c(I)n1Cc1cccc(CO)c1
Temperature: 65 °C
Yield: 93.2 %

Procedure:
To a stirred solution of 1 (0.20 g, 0.43 mmol) in DMF (2.5 mL) was added 4-(1H-Indol-3-yl)butan-1-ol (82 mg, 0.43 mmol) and K2CO3 (60 mg, 0.43 mmol) at room temperature. The resulting mixture was heated at 65° C. for 18 hours. After cooling to room temperature water (3 mL) was added, extracted with EtOAc, washed with brine, dried over MgSO4, and then purified by MPLC (gradient: Hex to EtOAc) to give 0.16 g of the titled compound as an inseparable mixture with 4-(1H-Indol-3-yl)butan-1-ol. It was intended to obtain an ether, but the reaction converted the Br to OH; 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.54 (s, 1H), 7.27-7.2 (m, 2H), 7.04 (s, 1H), 6.87 (d, J=7.0 Hz, 1H), 5.79 (s, 2H), 4.65 (s, 2H), and 3.77 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: Nc1cc(F)cc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccccn1
Yield: 43 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-ylamine (Intermediate 48) (125 mg, 0.77 mmol), pyridine-2-sulfonyl chloride Intermediate 18) (163 mg, 0.92 mmol), pyridine (0.12 ml, 1.54 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (100 mg, 43%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.CN(C)[CH:15]=[O:16].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[S:3][C:4]([CH:15]=[O:16])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1csc(Cl)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Cl)sc1C=O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-chloro-4-methylthiazole (0.3 g) in tetrahydrofuran (3 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 1.52 ml) dropwise at −70° C. under a nitrogen atmosphere, and the mixture was stirred for 20 minutes at −70° C. To the resultant mixture was added N,N-dimethylformamide (0.21 ml) at −70° C., and the mixture was stirred for 40 minutes. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (silica gel 10 g, n-hexane:ethyl acetate=10:1) to give 2-chloro-5-formyl-4-methylthiazole (231 mg).