Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[OH:20].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1c1ccc(F)cc1
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(F)cc1)C2

Procedure:
Reaction of 6,7-dichloro-5-hydroxy-2-(p-fluorophenyl)-1-indanone with ethyl bromoacetate according to the procedure of Example 1, STEP (a), affords the title compound. Crystallization from ethanol provides analytically pure material, m.p. 143°-144°.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:33]=[C:32]([C:34]([NH:36][OH:37])=[NH:35])[CH:31]=[CH:30][N:29]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:37][N:36]=[C:34]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([NH2:27])[CH:33]=4)[N:35]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: N=C(NO)c1ccnc(N)c1
Product: Nc1cc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)ccn1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (162 mg, 66%). MS (ISP) 492.1 [(M+H)+]; mp 277° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][NH:33][CH2:34][CH2:35][OH:36]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:33]([CH2:34][CH2:35][OH:36])[CH3:32])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CNCCO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Product: Cc1cc(F)ccc1-c1nc(N(C)CCO)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
Following the general procedure outlined in Example 126, the product of Example 48 (100 mg, 0.22 mmol), N-methylethanolamine (0.05 mL, 0.66 mmol) were reacted for 2 h to give the crude material, which was purified by preparative hplc to affored the title compound, 26 mg (27%). LC-MS: 441.2 (MH+, m/z), 2.19 (Rt, min).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>>[O:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:11][CH2:12]1
Reactant: O=Cc1ccccc1F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=Cc1ccccc1N1CCOCC1
Temperature: 125 °C
Yield: 63 %

Procedure:
A mixture of 2-fluorobenzaldehyde (0.5 mL, 4.8 mmol), morpholine (0.6 mL, 1.5 eq) and potassium carbonate (1.3 g, 2 eq) was heated in the microwave at 125° C. for 2.5 h. After evaporation, the residue was partitioned between water and DCM, the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 2-morpholinobenzaldehyde (0.57 g, 63%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:13][C:12]([C:15]#[CH:16])([CH3:14])[CH2:11][CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2].Br[C:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[S:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:13][C:12]([C:15]#[C:16][C:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[S:24][CH:23]=3)([CH3:14])[CH2:11][CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: Brc1csc2ccccc12
Reactant: C#CC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C#Cc1csc3ccccc13)O2
Temperature: 95 °C

Procedure:
A mixture of 0.544 g of rac-6-acetyloxy-2-ethynyl3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran, 0.64 g of 3-bromobenzothiophene, 90 mg of triphenylphosphine, 20 mg of cuprous iodide, 2 ml of triethylamine and 40 ml of dimethylformamide was stirred and degased by a stream of argon for 15 minutes. Palladium acetate, 30 mg, was then added and the mixture was heated at 95° C. for 5 hours. The reaction mixture was partitioned between saturated sodium bicarbonate solution and toluene. The organic phase was washed with water, dried and evaporated. The residue was chromatographed over 50 g of silica gel using toluene for elution. The combined clean fractions were crystallized from hexane to give the title compound with m.p. 96-99°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[F:28][C:29]([F:39])([F:38])[C:30]1[N:35]=[CH:34][C:33]([CH2:36][NH2:37])=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:37][CH2:36][C:33]2[CH:34]=[N:35][C:30]([C:29]([F:39])([F:28])[F:38])=[CH:31][CH:32]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=c1cc(NCc2ccc(C(F)(F)F)nc2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), [6-(trifluoromethyl)pyridin-3-yl]methanamine (86 mg, 0.49 mmol, 1.49 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-(bis(4-chlorophenyl)methyl)-4-(((6-(trifluoromethyl)pyridin-3-yl)methyl)amino)quinolin-2(1H)-one as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=[O:23])=[C:14]([F:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][OH:23])=[C:14]([F:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)c(C=O)nc3N21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)c(CO)nc3N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
To a solution of 0.58 g (4R,9aR)-7-fluoro-6-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 10 mL tetrahydrofuran was added 0.038 g lithium borohydride and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was evaporated to dryness and purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 0.468 g (4R,9aR)-7-fluoro-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as yellowish crystals; m.p.: 91–93° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCC(CO)C4)c3)ncnc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(C1CCC(CO)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h

Procedure:
To 3-[3-(hydroxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (60.4 mg, 0.129 mmol) dissolved in CH2Cl2 (2.0 mL) was added TFA (1.0 mL) and the reaction was stirred for 1 hour at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate (m/z=367). The trifluoroacetate ester of the hydroxymethyl of the cyclopentyl ring was also observed (m/z=463). The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (80 μL, 1.19 mmol). The resulting mixture was stirred for 16 hours at which point LCMS indicated complete reaction to the desired product. The solvent was removed and the residue was purified by chiral HPLC to provide four distinct diastereomers (20.2 mg total of four isomers, 46%). NOE experiments suggest that all isomers have cis geometry on the cyclopentyl ring. Isomers 1 and 2: 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.40 (m, 2H), 3.22 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.82 (m, 1H), 1.6-1.4 (m, 3H), 1.03 (m, 1H). Isomers 3 and 4: 1H NMR (400 MHz, CD3OD): δ 8.66 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.09 (m, 1H), 1.71 (m, 1H), 1.55-1.25 (m, 3H), 1.04 (m, 1H). MS (EI) m/z=337.1 (M+H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:24])([CH3:23])[C:16]([NH:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])=[CH:11][CH:10]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:23])([CH3:24])[C:16]([NH:18][CH2:19][CH:20]([CH3:21])[CH3:22])=[O:17])=[CH:11][CH:10]=1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccccc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccccc2CO)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 62 %

Procedure:
2-(2′-Formylbiphenyl-4-yl)-N-isobutyl-2-methylpropanamide (example 37) (190 mg, 0.59 mmol) was dissolved in anhydrous MeOH (6 mL) and the mixture was cooled to 0° C. A solution of NaBH4 (45 mg, 1.2 mmol) in anhydrous MeOH (4 mL) was then added to the solution. The mixture was stirred for 4 hrs at room temperature and then evaporated. The residue was dissolved in EtOAc and washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was successively purified on preparative RP HPLC (acetonitrile/water) and on silica gel (EtOAc/hexanes) and co-evaporated with ethanol to give 119 mg (62%) of white crystals. 1H NMR (400 MHz, dMSO): δ 0.72-0.74 (d, 6H), 1.47 (s, 6H), 1.67-1.70 (m, 1H), 2.82-2.86 (t, 2H), 4.37-4.38 (d, 2H), 5.01-5.1 (t, 1H), 7.17 (d, 1H), 7.27-7.36 (m, 7H), 7.53-7.55 (d, 1H); MS+H (326).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[CH:12]=[C:13]([C:17]([C:19]2[C:27]3[CH:26]=[N:25][CH:24]=[N:23][C:22]=3[N:21]([CH:28]([CH3:30])[CH3:29])[CH:20]=2)=[O:18])[CH:14]=[N:15][CH:16]=1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39](O)=[O:40])=[N:36][CH:37]=1>>[Br:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([NH:10][C:11]2[CH:16]=[N:15][CH:14]=[C:13]([C:17]([C:19]3[C:27]4[CH:26]=[N:25][CH:24]=[N:23][C:22]=4[N:21]([CH:28]([CH3:30])[CH3:29])[CH:20]=3)=[O:18])[CH:12]=2)=[O:40])=[N:36][CH:37]=1
Reactant: O=C(O)Cc1ccc(Br)cn1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Br)cn3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 1 with DIPEA using (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and (5-bromopyridin-2-yl)acetic acid to afford the title compound as a yellow solid in 45% yield, 75 mg. LCMS (System 9): Rt=2.97 min; m/z 479 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH:21][OH:22])=[NH:20])=[C:14]([Cl:23])[CH:13]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:40]1([O:46]C(Cl)=O)C=CC=CC=1.C(OCC)(=O)C>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[NH:20][C:40](=[O:46])[O:22][N:21]=2)=[C:14]([Cl:23])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC(=N)NO)c(Cl)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(Cc2noc(=O)[nH]2)c(Cl)c1
Temperature: 25 °C

Procedure:
2.3 g crude 2-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-N-hydroxy-acetamidine were dissolved in 30 ml dichloromethane. 0.46 ml pyridine and 0.71 ml phenylchloroformate were added and the mixture stirred at room temperature for ten minutes. The mixture was diluted by the addition of 150 ml ethyl acetate, washed with brine and dried over MgSO4. The solvent was evaporated in vacuo. The resulting residue was dissolved in 20 ml acetonitrile and 0.70 ml 1,8-Diazabicyclo[5.4.0]undec-7-ene were added. The mixture was stirred at room temperature for 10 minutes. The mixture was evaporated in vacuo and the resulting crude material was purified by reversed phase HPLC to obtain 820 mg 3-{4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-benzyl}-4H-[1,2,4]oxadiazol-5-one as an amorphous lyophilisate.
Reaction SMILES: [ClH:1].[CH2:2]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[S:27][C:22]3=[N:23][CH2:24][CH2:25][CH2:26][N:21]3[C:20]=2[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:18])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[OH-].[Na+]>C(O)C>[ClH:1].[CH2:2]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([C:19]2[S:27][C:22]3=[N:23][CH2:24][CH2:25][CH2:26][N:21]3[C:20]=2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:18])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCc1ccc(NC(=O)C2=C(CCC(=O)OCC)N3CCCN=C3S2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCc1ccc(NC(=O)C2=C(CCC(=O)O)N3CCCN=C3S2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
In 30 ml of ethanol was dissolved 720 mg of N-(4-octylphenyl)-3-(2-ethoxycarbonylethyl)-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide hydrochloride obtained in Example 79. To the solution was added 3.5 ml of 1N sodium hydroxide aqueous solution, followed by stirring at room temperature for 16 hours. The solvent was removed under reduced pressure. To the residue was added 1N hydrochloric acid to make acidic. The precipitated crystals were washed with diethylether to obtain 628 mg of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([CH:24]=O)=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].C[NH3+].[C:29]([BH3-])#[N:30].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([CH2:24][NH:30][CH3:29])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: COc1ccc(-c2cc(C=O)cn2S(=O)(=O)c2ccc(F)cc2)cc1
Agent: C[NH3+]
Agent: [Cl-]
Agent: [Na+]
Product: CNCc1cc(-c2ccc(OC)cc2)n(S(=O)(=O)c2ccc(F)cc2)c1
Yield: 44.6 %

Procedure:
Using 1-(4-fluorophenylsulfonyl)-5-(4-methoxyphenyl)-1H-pyrrole-3-carbaldehyde (0.28 g), methylammonium chloride (0.62 g) and sodium cyanoborohydride (0.15 g), a procedure as in Example 6 was performed to give the title compound as a colorless oil (yield 0.13 g, 44%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][NH:10]C(=O)C(F)(F)F)[CH2:4][O:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:21])[O:6][CH:5]([C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][NH2:10])[CH2:4][O:3]1
Reactant: CC1(C)OCC(c2ccccc2CNC(=O)C(F)(F)F)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OCC(c2ccccc2CN)O1
Temperature: 50 °C
Reaction time: 24 h
Yield: 101.6 %

Procedure:
To a mixture of 2.19 g of N-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)benzyl]-2,2,2-trifluoroacetamide and 22 ml of methanol was added 5.0 ml of a 2 M aqueous sodium hydroxide solution, followed by stirring at 50° C. for 24 hours. The reaction mixture was left to be cooled to room temperature and then concentrated under reduced pressure, and water was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure to obtain 1.52 g of 1-[2-(2,2-dimethyl-1,3-dioxolan-4-yl)phenyl]methanamine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]([OH:21])[C:18]([OH:20])=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.Cl>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([C:17](=[O:21])[C:18]([OH:20])=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2C(O)C(=O)O)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a scintillation vial containing (5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-hydroxy-acetic acid (0.35 g, 1.2 mmol) was added 15 mL DCM followed by the addition of Dess-Martin periodinane (0.61 g, 1.44 mmol). The reaction mixture was allowed to stir at room temperature for 20 minutes and poured into a separatory funnel containing 30 mL 0.5 M HCl. The layers separated and the aqueous layer extracted twice more with 50 mL DCM. The combined organic layers were washed with Brine, dried over MgSO4 and concentrated under vacuum to afford the desired product (purity >80% by NMR). No further purification was attempted. Expected mass=286. Observed mass=287.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C1COCCN1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCOCC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (100 mg, 0.38 mmol) in DCM (10 ml) was added DCC (95 mg, 0.46 mmol), DMAP (56 mg, 0.46 mmol), and stirred for 5 min at RT, morpholine (1 ml, 11.5 mmol) was added and stirred at 25 deg C. for 14 h. The reaction mixture was concentrated to dryness and The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 10 mg (Yield 5.8%) of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-morpholino ethanone as TFA salt.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Br:10])[C:3]=1[CH:4]=[O:5].[CH3:11][C:12]1([CH3:25])[CH2:23][C:22]2[CH:21]=[C:20]3[N:15]([CH2:16][CH2:17][NH:18][C:19]3=[O:24])[C:14]=2[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]3[C:20](=[CH:21][C:22]4[CH2:23][C:12]([CH3:11])([CH3:25])[CH2:13][C:14]=43)[C:19]2=[O:24])[C:3]=1[CH:4]=[O:5]
Reactant: CC1(C)Cc2cc3n(c2C1)CCNC3=O
Reactant: O=Cc1c(Br)cncc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1cncc(Br)c1C=O)C3=O
Temperature: 100 °C
Yield: 67.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 3,5-dibromoisonicotinaldehyde (400 mg, 1.5 mmol), 107e (155 mg, 0.76 mmol), and cesium carbonate (176 mg, 1.5 mmol). Xantphos (40 mg, 0.08 mmol) and Pd2(dba)3 (70 mg, 0.08 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with DCM:MeOH (20:1) to afford 107f (200 mg, 70%). MS: [M+H]+ 388.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([OH:26])[N:20]=1>>[OH:26][C:21]1[N:20]=[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[C:24]([CH3:25])=[CH:23][N:22]=1
Reactant: Cc1cnc(O)nc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: Cc1cnc(O)nc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 4-amino-2-hydroxy-5-methylpyrimidine (36 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.47 (brs, 1H), 8.59-8.54 (m, 2H), 7.28 (dd, J=8.1, 5.1 Hz, 1H), 6.59 (s, 1H), 5.18 (s, 2H), 1.70 (s, 3H).
Reaction SMILES: [CH2:1]([N:5]([CH2:15][C:16](Cl)=[CH2:17])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[S:7])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>O>[C:9]1([N:8]=[C:6]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:15]=[C:16]([CH3:17])[S:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(Cl)CN(CCCC)C(=S)Nc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCCn1cc(C)sc1=Nc1ccccc1
Temperature: 50 °C
Yield: 39.7 %

Procedure:
N-butyl-N-(2-chloro-2-propenyl)-N'-phenylthiourea (0.26 g) was added to 90% sulfuric acid (2.5 g) at room temperature with stirring, and the mixture was heated to 50° C. and stirred at the same temperature for 1.5 hour. After cooling, water was added to the reaction mixture, which was then neutralized by addition of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water. The solvent was removed by distillation under reduced pressure, which afforded 0.09 g of 2-(N-phenylimino)-3-butyl-5-methyl-4-thiazoline as an oil (34% yield).