Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[OH:35]O>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:35])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(B4OC(C)(C)C(C)(C)O4)ccc(F)c32)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
(1S,2S)-2-{4-[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 4, 1.31 g, 2.8 mmol) is suspended in acetic acid (8 mL) and hydrogen peroxide solution (35% in water, 0.97 mL, 11.2 mmol) is added. The mixture is stirred for 1 hour then diluted with water and extracted with ethyl acetate. The organic extracts are washed with water and brine, dried over sodium sulfate and the solvent removed. The residue is dried under vacuum to give the title compound (Yield 0.95 g). LC (METHOD 6): tR=0.57 min; Mass spectrum (ES+): m/z=357 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:3].[C:13]([OH:18])([CH2:16][CH3:17])([CH3:15])[CH3:14].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)[O:18][C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14]
Reactant: CCC(C)(C)O
Reactant: CSc1ccc(OC(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C)(C)OC(=O)Oc1ccc(SC)cc1
Reaction time: 2 h

Procedure:
One hundred ml of dichloromethane and 20.27 g (0.1 mol) of p-methylthiophenyl chloroformate prepared in the same manner as in Example 1 were placed in a flask, and 50 ml of a dichloromethane solution containing 8.15 g (0.1 mol) of tertamyl alcohol and 8.70 g (0.11 mol) of pyridine was dropped thereto at room temperature. The resulting mixture was then stirred for two hours. The reaction solution was washed with water to remove pyridine hydrochlorate, and the organic layer was concentrated under reduced pressure. Finally excessive pyridine was removed in vacuum whereupon 5.09 g of the desired product, tert-amyl p-methylthiophenyl carbonate was obtained as an oily material (yield 100%).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.Cl>C(#N)C>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([NH:20][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:22][CH:23]=1)([OH:27])=[O:26]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: C=C(C)C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Into a 1 liter flask 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester were added. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in a cold bath. Stirring was continued for 1 hour at room temperature. 137.1 g (1 mol) of 4-aminobezoic acid was added to the mixture. The mixture was heated for 2 hours at 50° C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 170.9 g of N-(4-carboxyphenyl)-methacrylamide.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.P(Cl)(Cl)(Cl)=O.N.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN
Reactant: CSc1nc(C)cc(O)n1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCNc1cc(C)nc(SC)n1

Procedure:
4-Hydroxy-6-methyl-2-methylthiopyrimidine (10.0 g, 64.13 mmol), prepared by the procedure described in Example 158A, was dissolved in ~45 mL (483 mmol, 7 equivalents) of phosphorus oxychloride under nitrogen and heated at reflux for 6.5 hours. The phosphorus oxychloride was distilled off and the remaining residue was dissolved in ether and poured onto ice. The aqueous phase was extracted several times with ether. The combined ether extracts were dried over magnesium sulfate and the 4-chloro-6-methyl-2-methylthiopyrimidine crystallized from the ether to afford 6.91 g (62%) as pale orange needles. 1H NMR (CDCl3, 300 MHz) δ 2.45 (s, 3H), 2.58 (s, 3H), 6.77 (s, 1H). MS (DCl/NH3) m/e 175 (M+H)+. The chloro-compound was reacted with n-butylamine by the procedure described in Example 158C to give 4-butylamino-6-methyl-2-methylthiopyrimidine.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(O)(=O)C>O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2cc(-c3ccccc3)on2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(-c2cc(-c3ccccc3)on2)cc1
Yield: 95.3 %

Procedure:
A mixture of methyl 4-(5-phenyl-3-isoxazolyl)benzoate (1.05 g), 6 M hydrochloric acid (10 ml) and acetic acid (20 ml) was heated under reflux for 5 hrs. After cooling, the reaction mixture was poured into water, and the crystals were washed with water to give 4-(5-phenyl-3-isoxazolyl)benzoic acid (0.95 g, yield 95%). Recrystallization from N,N-dimethylformamide-water gave colorless prism crystals. melting point: 297–298° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=O)[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:24])[CH2:9][CH2:8]3)[CH2:5]1.[ClH:25].Cl.[NH2:27][CH2:28][CH2:29][O:30][NH2:31]>>[ClH:25].[NH2:27][CH2:28][CH2:29][O:30][N:31]=[C:19]1[CH2:18][CH2:17][C@@:16]2([CH3:23])[CH:21]([C@@H:4]([CH2:3][O:2][CH3:1])[CH2:5][C@@H:6]3[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:24])[CH2:20]1
Reactant: NCCON
Reactant: COC[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Agent: Cl
Product: COC[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=NOCCN)CC12
Yield: 33 %

Procedure:
Prepared in 33% yield as described in Example 1 starting from 6α-methoxymethylandrostane-3,17-dione (II-ap, Prepn. 16) and 2-aminoethoxyamine dihydrochloride. The crude product was crystallized from Et2O/EtOAc. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.82 (bb, 3H), 4.06 (m, 2H), 3.22 (m, 2H), 3.20 (s, 3H), 3.05 (m, 1H), 3.02 (m, 2H), 2.45-0.60 (m, 20H), 0.89 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][C:10]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(N)c2)n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)n1
Yield: 78.4 %

Procedure:
To a solution of tert-butyl {6-[2-(3-aminophenyl)ethyl]pyridin-2-yl}carbamate (200 mg, 0.64 mmol) and 2,4,5-trichloropyrimidine (123 mg, 0.67 mmol) in N,N-dimethylformamide (2.9 mL) was added potassium carbonate (264 mg, 1.91 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered first to remove K2CO3, followed by quenching with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and then dried (Na2SO4), filtered and concentrated to give the residue, which was purified by silica gel column chromatography to give the desired product as a light brown gel (231 mg, 79%). LCMS for C17H16Cl2N5 [(M-Boc+H)+H]+: m/z=360.0, 362.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:7][CH2:6][C:5]([N+:32]([O-:34])=[O:33])([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([O:25]C5C=CC=CC=5)=[CH:21][CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.[CH2:36](OC1C=CC(O)=CC=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:5]2([N+:32]([O-:34])=[O:33])[CH2:6][O:7][C:2]([CH3:35])([CH3:1])[O:3][CH2:4]2)[CH:17]=[CH:16]3)=[CH:20][CH:21]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC1(C)OCC(c2ccc3cc(Oc4ccc(Oc5ccccc5)cc4)ccc3c2)([N+](=O)[O-])CO1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: CC1(C)OCC(c2ccc3cc(Oc4ccc(OCc5ccccc5)cc4)ccc3c2)([N+](=O)[O-])CO1
Yield: 41 %

Procedure:
5-(6-(4-(benzyloxy)phenoxy)naphthalen-2-yl)-2,2-dimethyl-5-nitro-1,3-dioxane was synthesized as per 2,2-dimethyl-5-nitro-5-(6-(4-phenoxyphenoxy)naphthalen-2-yl)-1,3-dioxane (Example 243) in 41% yield using 4-(benzyloxy)phenol as the reagent.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=4)[CH:3]=3)[NH:7][N:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: OB(O)c1cccc(F)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4cccc(F)c4)cc23)CC1
Yield: 21.2 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indazole-7-carboxamide (Intermediate 13) (30 mg, 0.072 mmols), 3-fluorophenyl boronic acid (30 mg, 0.216 mmols), potassium carbonate (60 mg, 0.433 mmol), and Pd(PPh3)4 (8 mg, 0.0072 mmol) in dioxane (2 mL) and water (1 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (6.57 mg, 21%)
Reaction SMILES: S=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:15])=O>CN(C=O)C.C(Cl)Cl>[Cl:15][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: N#Cc1ccc2oc(=S)[nH]c2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2oc(Cl)nc2c1
Temperature: 67.5 °C
Yield: 65 %

Procedure:
To a mixture of 2-thioxo-2,3-dihydrobenzooxazole-5-carbonitrile (2.56 g, 14.5 mmol) and thionylchloride (14.1 mL) was added two drops of DMF. The mixture was heated at 65-70° C. for 1 h. Then the mixture was cooled to rt and diluted with CH2Cl2. The solvent and excess thionylchloride were removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 20% EtOAc in Petroleum ether) to give 2-chlorobenzo-oxazole-5-carbonitrile 1.69 g (65%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1C=CC=CC=1.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)CBr
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
4-Benzylpiperazine(3.3 ml, 18.9 mmol) was added to a solution of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), which was then stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.38 g of the titled compound. (Yield 100%).
Reaction SMILES: [CH3:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[C:4]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])[CH:3]=1.[CH3:31][CH:32]1[CH2:34][O:33]1>N1C=CC=CC=1>[OH:33][CH:32]([CH3:34])[CH2:31][N:21]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:23])=[O:24])[C:4]1[CH:3]=[C:2]([CH3:1])[C:19]([CH3:20])=[CH:18][C:5]=1[O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: CC1CO1
Reactant: COC(=O)c1ccc(COc2cc(C)c(C)cc2NS(=O)(=O)c2ccccn2)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(CC(C)O)S(=O)(=O)c2ccccn2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
680 mg of methyl 4-({4,5-dimethyl-2-[(pyridin-2-ylsulfonyl)amino]phenoxy}methyl)benzoate was dissolved in 6.45 mL of pyridine, and 1.13 mL of 2-methyloxirane was added thereto, followed by stirring at 80° C. overnight in a sealed tube. The reaction liquid was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 99:1) to obtain 466 mg of methyl 4-({2-[(2-hydroxypropyl)(pyridin-2-ylsulfonyl)amino]-4,5-dimethylphenoxy}methyl)benzoate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([CH2:28][C:29]5[CH:30]=[C:31]6[C:36](=[CH:37][C:38]=5[F:39])[N:35]=[CH:34][CH:33]=[CH:32]6)=[CH:26][N:27]=4)[N:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[F:39][C:38]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[N:35]2)=[CH:30][C:29]=1[CH2:28][C:25]1[N:23]2[N:24]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[CH:20]=[CH:21][C:22]2=[N:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc4ncc(Cc5cc6cccnc6cc5F)n4n3)cn2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1cc2ncccc2cc1Cc1cnc2ccc(-c3cnn(C4CCNCC4)c3)nn12

Procedure:
4-{4-[3-(7-Fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (Stage 180.1, 850 mg, 1.611 mmol) was stirred 1 h at rt in dioxane (15 mL) with HCl in dioxane (4 M, 4,03 mL). The RM was then basified with saturated NaHCO3 aqueous sol. and the dioxane was evaporated. The resulting aqueous sol. was extracted 3 times with DCM containing 10% EtOH. Combined organic layers were dried and evaporated and the residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, DCM/MeOH with ammonia=100:0->90:10) to afford the title compound (tR 3.04 min (conditions 3), MH+=428).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)COc1ccccc1-c1ccccc1

Procedure:
In 10 ml of acetonitrile, 1.0 g of o-phenylphenol and 1.29 ml of ethyl bromoacetate were added in the presence of 1.76 ml of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and the resultant mixture was refluxed for 8 hr. The reaction mixture was treated similarly to that in Example 28 (Process 2) to give 1.46 g of ethyl o-phenylphenoxyacetate. The ester was dissolved in 30 ml of ethanol, mixed with 10.8 ml of 1N-NaOH aqueous solution and stirred for 12 hr. The reaction mixture was evaporated under reduced pressure, acidified by the addition of 1N-HCl and extracted with ethyl acetate. The extract was washed with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure and o-phenylphenoxyacetic acid was crystallized as DCHA salt from ether with the yield of 1.59 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[CH:26]=[C:27]([S:31]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:26]=[C:27]([S:31]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccc(S(=O)(=O)NC(C)(C)CO)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (336 mg, 1.0 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.6) (308 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (269 mg, 48%). MS (ISN) 561.3 [(M−H)−]; mp 204° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1.[OH-].[Na+]>ClC(Cl)C>[CH2:1]([NH:8][CH2:32][C:29]1[CH:30]=[CH:31][O:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: c1ccc(CNCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzylamine (16 g, 150 mmol) was dissolved in dichloroethane (320 ml), and the solution was mixed with acetic acid (77 ml, 1.3 mol), sodium triacetoxyborohydride (57 g, 590 mmol) and 3-furaldehyde (13 g, 130 mmol) and stirred at room temperature for 16 hours. 5 N Sodium hydroxide aqueous solution was added to the reaction solution until it became basic, and the reaction product was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 19 g (100 mmol, 77% in yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][CH2:24][CH2:25][F:26].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][F:26])[C:5]2=[CH:4][CH:3]=1
Reactant: FCCCCBr
Reactant: COC(=O)c1cc2nc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2nc(Cl)ccc2n1CCCCF
Temperature: 60 °C

Procedure:
To a solution of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate 11-c (2.9 g, 12.2 mmol) in DMF (50 mL) were added successively cesium carbonate (4 g, 12.2 mmol) and 1-bromo-4-fluorobutane (1.3 mL, 12.2 mmol). The resulting mixture was heated at 60° C. overnight. The reaction mixture was allowed to cool down to room temperature then poured into iced water and the product was extracted 3 times with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to give the targeted product 11-d as a yellowish solid. The product was used as such in the next step. m/z=313 (M+H)+, Cl pattern.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:18].O1CCOCC1>CO>[ClH:18].[NH:8]1[CH2:13][CH2:12][C:11]([CH2:16][OH:17])([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CO)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: OCC1(CO)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (1-tert-butoxycarbonylpiperidine-4,4-diyl)dimethanol, 4M HCl-dioxane solution and MeOH was stirred for two hours at room temperature to give piperidine-4,4-diyldimethanol hydrochloride.
Reaction SMILES: [NH2:1][C:2]1([F:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:3]1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[Br:17][CH2:18][C:19](Br)=[O:20]>ClCCl.O>[Br:17][CH2:18][C:19]([NH:1][C:2]1([F:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:3]1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])=[O:20]
Reactant: O=C(Br)CBr
Reactant: NC1(F)C=CC=CC1C(=O)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)NC1(F)C=CC=CC1C(=O)c1ccccc1
Temperature: -10 °C

Procedure:
To a cooled (-10° C.), stirred suspension of 2-amino-2-fluorobenzophenone (19.40 g, 0.090 mol) in dichloromethane (130 mL) and water (10 mL) was added a solution of bromoacetylbromide (9.0 mL, 0.104 mol) in dichloromethane (30 mL), keeping the temperature of the reaction mixture at -10° C. After addition the reaction mixture was stirred whilst warming to room temperature (21/2hours). The organic layer was collected, washed with water (2×100 mL) then concentrated to approximately 70 mL. Hexane (70 mL) was added and the required product collected by filtration (25.6 g, 83%): mp 120°-121° C. Rf 0.30 in diethyl ether/n-hexane (1:1) on silica; 1H NMR (CDCl3) δ4.05 (2H,s), 7.10-7.64 (7H, m), 8.70 (1H, d, J=8 Hz), 11.95 (1H, broad s); MS, m/z 335 (M+ ). Anal. Calcd. for C15H11BrFNO2 :C, 53.59; H, 3.30; N, 4.17. Found: C, 53.32; H, 3.33; N, 4.00.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH2:5][CH2:6]Cl)[CH3:2].[Si:8]([CH3:12])([CH3:11])(Cl)[Cl:9]>BrBr.CCOCC>[CH2:1]([S:3][CH2:4][CH2:5][CH2:6][Si:8]([Cl:9])([CH3:12])[CH3:11])[CH3:2]
Reactant: CCSCCCCl
Reactant: C[Si](C)(Cl)Cl
Agent: BrBr
Solvent: CCOCC
Product: CCSCCC[Si](C)(C)Cl

Procedure:
3-Ethylthiopropyl chloride (7.00 g, 50 mmol) was dropped slowly into Mg turnings (1.22 g, 50 mmol) activated with 2 drops of Br2 in Et2O (70 mL). After 12 h of reflux the Grignard reagent was added to Me2SiCl2 (25.8 g, 200 mmol) in diethyl ether (100 mL). After refluxing for 18 h under mechanical stirring the Mg salts were filtered off, washed with Et2O (2×25 mL), and the solvent was evaporated from the combined filtrates. The residue was fractionally distilled: 45° C./0.01 torr, 4.20 g, 42%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([O:23]C)=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2C(=O)O)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
A mixture of 4-(2-methoxycarbonyl-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (330 mg; 0.99 mmol; 1 eq.) and 1M NaOH (2 mL; 2 mmol; 2 eq.) in EtOH (3 mL) was stirred at 60° C. for 16 hours. The pH was made acidic with 1M HCl and the mixture extracted with DCM (2×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo to afford the title compound (295 mg, 93%) as a white solid. HPLC (max plot) 99.8%; Rt 4.40 min. 1H NMR (300 MHz, CDCl3) δ 11.17 (s, 1H), 8.07 (dd, J=7.9, 1.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.31 (td, J=7.6, 1.3 Hz, 1H), 7.21 (dd, J=7.7, 1.3 Hz, 1H), 4.07 (s, 2H), 2.98 (d, J=6.8 Hz, 2H), 2.62 (t, J=12.7 Hz, 2H), 1.80-1.57 (m, 3H), 1.45 (s, 9H), 1.28-1.14 (m, 2H).