Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[CH3:11][O-:12].[Na+].CO>CN(C=O)C>[CH3:11][O:12][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1
Reactant: COc1ccc(I)nc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1OC
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-3-methoxy-6-iodopyridine (3-3, 34 g, 108 mmol) in DMF (65 mL) was added sodium methoxide in methanol (37 mL, 162 mmol, 4.37M) and heated to 100° C. The mixture was stirred for 10 minutes and partitioned between saturated NaHCO3 and DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica (0 to 20% EtOAc in hexanes) to afford the title compound (3-4) as a white powder. ESI+MS[M+H]+C7H8INO2: 265.8 found, 266.0 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3O[CH:23]=[CH:24][CH:25]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.NC(C1N=NC(NC2C=CC(OC)=CC=2)=NC=1)C.[S:44]1C=CC=C1C(Cl)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[S:44][CH:23]=[CH:24][CH:25]=3)=[O:20])[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1cccs1
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccco3)nn2)cc1
Agent: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3cccs3)nn2)cc1

Procedure:
In a similar manner as described for Intermediate 59, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and thiophene-2-carbonyl chloride (0.048 mL, 0.45 mmol) to afford N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (115 mg) as a yellow solid. MS m/z 356 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]([CH3:7])[N:4]([CH2:8][C:9]([OH:11])=O)[N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH:20]1[O:24][N:23]=[C:22]([C:25]2[N:26]=[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[CH:20]1[O:24][N:23]=[C:22]([C:25]2[N:26]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][N:4]4[CH:5]([CH3:7])[CH2:6][C:2]([CH3:1])=[N:3]4)[CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH2:21]1
Reactant: Fc1cccc(F)c1C1CC(c2csc(C3CCNCC3)n2)=NO1
Reactant: CC1=NN(CC(=O)O)C(C)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=NN(CC(=O)N2CCC(c3nc(C4=NOC(c5c(F)cccc5F)C4)cs3)CC2)C(C)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 4,5-dihydro-3,5-dimethyl-1H-pyrazole-1-acetic acid (i.e. the product of Step B) (0.10 g, 0.64 mmol), 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]piperidine (i.e. the product of Example 1, Step D) (175 mg, 0.5 mmol), N3-(ethylcarbodimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride (191 mg, 1.0 mmol), 1-hydroxybenzotriazole (5 mg, 0.037 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dichloromethane (4 mL) was stirred at room temperature. After 6 h, more N3-(ethylcarbodimidoyl)-N1,N1-dimethyl-1,3-propanediamine hydrochloride (191 mg, 1.0 mmol) and triethylamine (0.14 mL, 1.0 mmol) were added to the reaction mixture. After 3 days, the reaction mixture was diluted with dichloromethane, washed with saturated aqueous ammonium chloride solution and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography on silica gel (0 to 100% gradient of ethyl acetate in hexanes, and then 20% methanol in ethyl acetate as eluant) to provide the title compound, a compound of the present invention, as a tan solid (124 mg).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:29])[N:18]([C@@H:22]4[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]4[F:28])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:40]=O>>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:29])[N:18]([C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:40])[CH2:24][C@H:23]4[F:28])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Product: CN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoro-1-methylpiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[trans-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 274) and formaldehyde following General Procedure R.
Reaction SMILES: Br.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl>N1C=CC=CC=1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(Br)cc3)cs2)cc1

Procedure:
A mixture of 4.0 g of 4-(4-bromophenyl)-thiazol-2-ylamine hydrobromide with 2.5 g of p-toluenesulfonyl chloride was stirred overnight with 15 ml of pyridine. The resulting, red colored suspension was poured into 180 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and chromatographed on 100 g of Kieselgel 60 with diethyl ether/hexane/methylene chloride (1:1:1) as the eluent. The product-containing fractions were concentrated and the residue was recrystallized twice from 60% ethanol. 0.8 g of N-[4-(4-bromo-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon cooling.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH:6]1[CH:7]=[CH:8][C:9]2[O:16][C:14](=[O:15])[CH2:13][CH2:12][C:10]=2[CH:11]=1>>[CH2:1]([N:3]([CH2:4][CH3:5])[C:14](=[O:15])[CH2:13][CH2:12][C:10]1[CH:11]=[CH:6][CH:7]=[CH:8][C:9]=1[OH:16])[CH3:2]
Reactant: O=C1CCc2ccccc2O1
Reactant: CCNCC
Product: CCN(CC)C(=O)CCc1ccccc1O
Yield: 113.8 %

Procedure:
Diethylamine (98.5 g) and dihydrocoumarin (20.0 g) were refluxed for 4 hours. Excess diethylamine was removed in vacuo to leave 34.0 g of N,N-diethyl-3-(2-hydroxyphenyl) propionamide. 1H NMR (CDCl3): 7.26-7.03 (m, 2H), 6.91 (dd, 1H), 6.81 (td, 1H), 3.37 (quartet, 2H), 3.26 (quartet, 2H), 2.95 (m, 2H), 2.71 (m, 2H), 1.10 (quartet, 6H).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]1[C:29]([CH2:30][CH3:31])=[C:28]([CH3:32])[C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:6]([CH3:33])[C:5]=1[CH2:34][CH3:35].[CH2:36]([O:38][C:39](=[O:50])[CH:40]=[C:41]([CH3:49])[CH:42]=[CH:43][CH:44]=[C:45]([CH:47]=O)[CH3:46])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:50])[CH:40]=[C:41]([CH3:49])[CH:42]=[CH:43][CH:44]=[C:45]([CH3:47])[CH:46]=[CH:8][C:7]1[C:6]([CH3:33])=[C:5]([CH2:34][CH3:35])[C:4]([O:3][CH3:2])=[C:29]([CH2:30][CH3:31])[C:28]=1[CH3:32])[CH3:37]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: CCc1c(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(CC)c1OC
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)c(CC)c(OC)c(CC)c1C

Procedure:
4-methoxy-3,5-diethyl-2,6-dimethyl-benzyl-triphenylphosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce the 9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester which is converted by the procedure of Example 7 to 9-(4-methoxy-3,5-diethyl-2,6-dimethyl-phenyl)-acid, m.p: 153°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([OH:55])[C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[C:49]([F:48])=[CH:54][CH:53]=[CH:52][C:51]=1[O:55][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: CC(=O)NCCc1c(O)cccc1F
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cccc(F)c2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.27 g of N-[2-(2-fluoro-6-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.58 (EtOAc); Rt=5.57.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[C:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21](=[O:29])(=[O:28])[N:20]=1>O1CCOCC1>[O:28]=[S:21]1(=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:20]1
Reactant: CCOC(=O)CCCN
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC1=NS(=O)(=O)c2ccccc21
Reaction time: 0.08 h

Procedure:
4.07 ml (29.2 mM) of triethylamine is added to 5.0 g. (29.2 mM) of ethyl 4-aminobutyrate hydrochloride, suspended in 75 ml of dioxane. After stirring for 5 minutes, 5.88 g. (29.2 mM) of 3-chloro-1,2-benzisothiazole 1,1-dioxide is added and the mixture is refluxed for one hour. The solvent is evaporated in vacuo and the residue is taken up in chloroform, washed with water, and evaporated to dryness. The residual 4-[(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]-butanoic acid, ethyl ester is recrystallized from 40 ml. of methanol/water, yield 3.72 g., m.p. 125°-127°.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[BH4-].[Na+].[C:17](O)(=O)[CH3:18]>C1COCC1>[CH2:17]([N:6]1[CH2:5][CH2:4][CH:3]2[C:8](=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[CH:11][CH:2]2[Br:1])[CH2:7]1)[CH3:18]
Reactant: O=[N+]([O-])c1ccc(Br)c2ccncc12
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCC2C(=C([N+](=O)[O-])C=CC2Br)C1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 5-bromo-8-nitroisoquinoline (1 g, 3.95 mmol) in 20 mL THF was cooled to 0° C. and treated sequentially with sodium borohydride (0.75 g, 19.83 mmol) followed by the slow addition of acetic acid (20 mL). The reaction mixture was allowed to warm to room temperature, and an additional 2 equiv. of sodium borohydride was added. After quenching with water and treatment with sodium hydroxide solution to make basic, the reaction mixture was extracted with ethyl acetate. The organic residue was chromatographed on silica gel (25% ethyl acetate in hexane) to give the N-ethyl-5-bromo-8-nitrotetrahydroisoquinoline (0.8 g, 70% yield).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:9][C:8]2=[O:23])=[CH:4][CH:3]=1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl>[Br:33][C:9]1[C:8](=[O:23])[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=2)[C:12]([CH3:13])=[CH:11][C:10]=1[NH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(NCc2ccc(F)cc2)cc(=O)n1Cc1ccc(F)cc1
Solvent: ClCCl
Product: Cc1cc(NCc2ccc(F)cc2)c(Br)c(=O)n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.1 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(1H)-one (0.2857 g, 0.84 mmol) in MeCl2 was added NBS (0.156 g, 0.88 mmol). The reaction stirred at room temperature under nitrogen for 45 minutes. The reaction mixture was diluted with MeCl2 and washed with NaHCO3. The organic extracts were washed with water, dried over Na2SO4, and concentrated to afford the desired product (0.3242 g, 92%) as a yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.32 (q, 2H), 7.04 (m, 6H), 5.91 (s, 1H), 5.28 (s, 2H), 4.50 (s, 2H), 2.17 (s, 3H); ES-HRMS m/z 419.0549/421.0537 (M+H calculated for C20H18N2OBrF2 requires 419.0565/421.0547).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9].[CH3:15][C:16](=O)[CH3:17].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[NH:10][C:16]1([CH3:17])[CH3:15]
Reactant: NC(=O)c1ccccc1NCCCCl
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CC1(C)NC(=O)c2ccccc2N1CCCCl

Procedure:
A mixture of 10 parts of 2-[(3-chloropropyl)amino]benzamide, 16 parts of 2-propanone, 1 part of 4-methylbenzenesulfonic acid and 40 parts of ethanol is stirred and refluxed overnight. The reaction mixture is evaporated and the oily residue is stirred in 2,2'-oxybispropane. The product is filtered off and dried, yielding 10 parts of 1-(3-chloropropyl)-2,3-dihydro-2,2-dimethyl-4(1H)-quinazolinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][C:4]=1[F:15].N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:14]=[C:13]2[C:6](=[CH:5][C:4]=1[F:15])[NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH:12][C:22](=[O:24])[CH3:23]
Reactant: COc1cc2c(CCN)c[nH]c2cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1cc2c(CCNC(C)=O)c[nH]c2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 0.75 grams (3.6 mmole) of the tryptamine, 2.0 ml. of pyridine, and 8.0 ml. of benzene was prepared. Acetic anhydride (1.0 ml.) was slowly added. The mixture was stirred at room temperature for 4 hours, and the solvents then were removed in vacuo with moderate heating. The resulting crystalline residue was dissolved in a 1:1 mixture of warm ethyl acetate and chloroform. The solution was washed with water, then with sodium chloride solution, and then dried over sodium sulfate. The solvents were removed in vacuo. The crystalline residue was boiled in benzene for a few minutes. The mixture was allowed to stand at room temperature for several hours, and the resulting product was collected by filtration and dried to obtain 0.81 grams (90 percent) of N-[2-(5-methoxy-6-fluoroindol-3-yl)ethyl]acetamide, m.p. 158°-159° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([F:12])[CH:6]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(OCc2ccccc2)c(F)c1
Temperature: 60 °C
Yield: 86.6 %

Procedure:
To a solution of (3-fluoro-4-hydroxy-phenyl)-acetic acid methyl ester (15 g, 54.3 mmol) and benzyl bromide (9.28 g, 54.3 mmol) in DMF (50 mL), was K2CO3 (7.24 g, 54.3 mmol) added at an ambient temperature. The reaction mixture was heated to 60° C. and maintained for 2 hours. The reaction was cooled to room temperature and poured into H2O (150 mL). The organic compound was extracted with ether (150 mL) and washed with sat NaHCO3 (100 mL). The ether layer was dried over MgSO4, and concentrated under vacuum to afford the desired compound (12.9 g, 87.9%) as a white crystal. The crude compound was used for the next step without further purification. 1H NMR (400 Mz, DMSO-d6) δ 7.41-7.49 (m, 5H), 7.15-7.23 (m, 2H), 7.02-7.04 (m, 1H), 5.19 (s, 2H), 3.65 (s, 2H), 3.63 (s, 3H). LCMS 273.4 [MH+].
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12](Cl)=[N:11][CH:10]=1.[NH:34]1[CH:38]=[N:37][CH:36]=[N:35]1>>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C:8](=[O:23])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)=[N:11][CH:10]=1
Reactant: Cc1ccccc1-c1cc(Cl)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1nc[nH]n1
Product: Cc1ccccc1-c1cc(-n2cncn2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 130 °C
Reaction time: 36 h
Yield: 87.3 %

Procedure:
A mixture of 1.00 g (2.05 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-6-chloro-N-methyl-4-o-tolyl-nicotinamide and 1.42 g (20.5 mmol) 1,2,4-triazole was stirred at 130° C. for 36 h. After cooling to room temperature the crude mixture was purified by flash chromatography to give 0.93 g (87%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=2)[C:9]([C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:23])[NH:7][C:6]=1[CH:24]=O)=[O:4].Cl.[NH2:27]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:24]([C:6]1[NH:7][C:8]([CH3:23])=[C:9]([C:19]([O:21][CH3:22])=[O:20])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[CH:18])[CH:12]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4])#[N:27]
Reactant: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C=O)=C2C(=O)OC)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: C#Cc1cccc(C2C(C(=O)OC)=C(C)NC(C#N)=C2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
In 16 ml of acetic acid was dissolved 1.87 g (5.5 mmol) of 3,5-dimethoxycarbonyl-2-formyl-1,4-dihydro-6-methyl-4-(3 -ethynylphenyl)pyridine obtained in Example 15. Thereto were added 0.45 g (6.5 mmol) of hydroxylamine hydrochloride and 0.67 g (8.2 mmol) of sodium acetate. The admixture was stirred for 2.5 hours at room temperature. Then 1.96 g (19.2 mmol) of acetic anhydride was added thereto, and the admixture was reacted for 1.5 hours at room temperature, further for 4 hours at 95°-100° C. After completing the reaction, the reaction solution was concentrated under reduced pressure, water was added to the residue. After neutralization of the reaction mixture with saturated solution of sodium hydrogencarbonate, the reaction mixture was extracted with ethyl acetate several times. The organic layer thereof was washed with water, dehydrated and concentrated. The residue was purified by subjecting to silica gel column chromatography [eluent: benzene-ethyl acetate (10 : 1)] and recrystallized from the mixture of ethyl acetate and n-hexane to give 1.2 g of the desired compound as yellow prism crystals (yield: 66.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][O:29][CH2:30][C:31](O)=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH:35][CH3:36]>>[CH3:34][N:35]([CH3:36])[C:31](=[O:32])[CH2:30][O:29][CH2:28][C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:26])[CH3:27])[N:17]=2)=[O:15])[CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CNC
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](COCC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](COCC(=O)N(C)C)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from [((2S,4S)-1-(tert-Butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)methoxy]acetic acid (step 1 of Example 21) and dimethylamine.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][C:5]=2[N:6]=1.[C:13]1(C)C=CC(S(OC)(=O)=O)=CC=1>CC#N>[OH:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([S:1][CH3:13])=[N:6][C:5]=2[CH:7]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc2sc(S)nc2c1
Solvent: CC#N
Product: CSc1nc2cc(O)ccc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a 250 mL flask was added 2-mercapto-5-methoxybenzothiazole (5.1 g, 26 mmol), MeCN (63 mL), methyl p-toluenesulfonate (4.8 g, 26 mmol) and TEA (4.4 mL, 31 mmol). After stirring 16 h at ambient temperature, the solution was concentrated under reduced pressure. The crude material was diluted with EtOAc (200 mL), washed with water (2×75 mL), dried over Na2SO4, filtered, and concentrated. The resulting viscous oil was dissolved in DCM (40 mL), and transferred to an argon-purged 250 mL flask. The solution was cooled to −78° C. prior to the addition of a 1.0 M BBr3 solution in DCM (64 mL). The reaction suspension was allowed to warm to room temperature. After 16 h the reaction solution was cooled to −78° C. and quenched by addition of MeOH (100 mL). The resulting precipitates were isolated by vacuum filtration to yield 5-hydroxy-2-methylthio-benzothiazole (3.9 g, 76%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[O:10])(=[O:3])[CH3:2].[Cl-].[CH3:12][NH2+]C.C=O>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8](=[CH2:12])[CH:9]=[O:10])(=[O:3])[CH3:2]
Reactant: C[NH2+]C
Reactant: CC(=O)OCCCCC=O
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCCOC(C)=O

Procedure:
10 g (69.4 mmol) of 5-acetoxypentanal, 6.37 g (78.2 mmol) of dimethylammonium chloride and 6.1 ml (81.2 mmol) of 37% formaldehyde solution are refluxed for 11/2 hours (bath temperature ~110° C.) with stirring. The mixture is allowed to cool and is extracted three times with ether; the organic phases are combined, dried over MgSO4, filtered and concentrated by evaporation. 5-acetoxy-2-methylenepentanal is obtained in the form of a yellowish oil which can be reacted without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)#[CH:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(N(CC)CC)C>CC(N(C)C)=O>[F:30][C:29]([F:32])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)=[N:7][CH:8]=2)=[N:24][CH:25]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C#Cc3ccc(C(F)(F)F)cn3)cn2)CC1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution of tert-butyl 4-(5-ethynylpyridin-2-yl)piperazine-1-carboxylate (509 mg, 1.77 mmol), 2-Bromo-5-trifluoromethylpyridine (400 mg, 1.77 mmol), triethylamine (0.74 mL, 5.31 mmol), and cuprous iodide (135 mg, 0.71 mmol) in DMA (20 mL) at 25° C. was added tetrakistriphenylphosphine palladium (0) (102 mg, 5 mol %). The reaction was then stirred for 1 hour. Volatiles were removed in vacuo, and the residue was azeotroped with toluene (2×10 mL). The residue was then dissolved in CH2Cl2 (10 mL) and washed with water (10 mL). The layers were then separated and the aqueous phase extracted with CH2Cl2 (2×100 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 25% EtOAc in hexanes) to give tert-butyl 4-(5-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridin-2-yl)piperazine-1-carboxylate as a yellow solid (729 mg, 1.68 mmol, 95%).