Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21](CC2C=CC=CN=2)[C:20]1=[O:38]>>[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21]([CH2:2][C:3]2[CH:7]=[C:6]([CH3:8])[O:5][N:4]=2)[C:20]1=[O:38]
Reactant: Cc1cc(CBr)no1
Reactant: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(CN2C(=O)N(Cc3c(F)cccc3Cl)c3ccccc3S2(=O)=O)no1

Procedure:
The title compound (0.16 g, 0.37 mmol) was prepared from (IntE1) (0.3 g, 0.88 mmol), 3-(bromomethyl)-5-methyl-1,2-oxazole (0.11 g, 0.63 mmol) and Cs2CO3 (0.86 g, 2.64 mmol) using the methods of (128).
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3](O)=[O:4].O.[NH3:33]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([NH2:33])=[O:4]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: N
Solvent: O
Product: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(N)=O

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and ammonia water (28% ammonia water).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:6]1[N:7]=[C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)[S:9][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: OB(O)c1cccc(F)c1F
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(F)c4F)c(C(=O)O)s3)c2cc1OC
Yield: 39 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 2,3-difluorophenylboronic acid (23.7 mg, 0.15 mmol) gave 4-(2,3-Difluoro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (16.2 39%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.81 (br.s., 1 H); 8.83 (s, 1 H); 7.74 (s, 1 H); 7.52-7.64 (m, 2 H); 7.40 (s, 1 H); 7.33-7.39 (m, 1 H); 3.85 (s, 3 H); 3.83 (s, 3 H). MS m/z 418 (M+1).
Reaction SMILES: [NH2:1][C:2](=[N:19][OH:20])[C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:5]([F:18])[CH:4]=1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28](O)=O)[CH:25]=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]>>[CH3:21][C:22]1[CH:27]=[C:26]([C:28]2[O:20][N:19]=[C:2]([C:3]3[CH:17]=[CH:16][C:6]([O:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[C:5]([F:18])[CH:4]=3)[N:1]=2)[CH:25]=[CH:24][C:23]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(N)=NO)cc1F
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(OCC(=O)OC(C)(C)C)c(F)c3)no2)cc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 49 (142.14 mg; 0.50 mmol) and Intermediate 3 (135.76 mg; 0.60 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound as a colorless oil. LC/MS (Method B): 475.4 (M+H)+. HPLC (Method A) Rt 6.78 min (Purity: 99.3%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl

Procedure:
A mixture of 2,3,5-trichlorobenzoic acid (90 g, 0.4M) and dimethylformamide (1 ml) in thionyl chloride (200 ml) was heated to reflux for 2 hours. The cooled solution was evaporated down in vacuo and the residue distilled under nitrogen. Yield 89.2 g (90%), b.p. 158°-160° C. at the pressure of 30 mm of mercury.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)[CH3:3].[N:12]#[C:13]Br>C(O)C.O>[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:13]([NH2:12])=[N:11][N:10]=2)[N:9]=1)[CH3:3]
Reactant: N#CBr
Reactant: CCc1ccc(NN)nn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1ccc2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Ethylpyridazin-3-yl)hydrazine hydrochloride (2 g) was initially charged in a mixture of ethanol (30 ml) and water (6 ml) while stirring at RT. Thereafter, cyanogen bromide was cautiously added dropwise (2.4 g dissolved in 7.5 ml of ethanol and 1.5 ml of water). After stirring at RT for one hour, the mixture was left to stand overnight and, the next day, stirred for 4 further hours. The solvent was then drawn off and the residue was purified by means of preparative HPLC (met. C). The clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 830 mg of the title compound were obtained. The aqueous potassium carbonate phase was likewise freeze-dried, then taken up with a little water and extracted five times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. A further 180 mg of the title compound were obtained.
Reaction SMILES: C(OC(=O)[N:7]([N:11]1[C:20]([CH2:21][Br:22])=[C:19]([C:23](=[O:37])[NH:24][C@@H:25]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[C:18]2[C:13](=[C:14]([F:38])[CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:39])[CH2:8][CH2:9][CH3:10])(C)(C)C>ClCCCl.FC(F)(F)C(O)=O>[CH:33]1([C@H:25]([NH:24][C:23]([C:19]2[C:18]3[C:13](=[C:14]([F:38])[CH:15]=[CH:16][CH:17]=3)[C:12](=[O:39])[N:11]([NH:7][CH2:8][CH2:9][CH3:10])[C:20]=2[CH2:21][Br:22])=[O:37])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: CCCN(C(=O)OC(C)(C)C)n1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCNn1c(CBr)c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c2cccc(F)c2c1=O

Procedure:
0.15 mg (3-Bromomethyl-4-{[(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-8-fluoro-1-oxo-1H-isoquinolin-2-yl)-propyl-carbamic acid tert-butyl ester was stirred at room temperature over night in 2 mL 1,2-dichloroethane and 2 mL trifluoroacetic acid. The reaction mixture was concentrated in vacuo to give the title compound.
Reaction SMILES: [I:1][C:2]1[C:3]([NH2:17])=[N:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C>[Si:23]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([I:1])[C:3]([NH2:17])=[N:4][C:5]2=[O:16])[CH2:8][C@@H:9]1[OH:10])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a solution of 5-iodo-2′-deoxycytidine (2.2 g, 6.23 mmol) in DMF (130 ml) was added imidazole (467 mg, 6.85 mmol). The mixture was cooled at 0° C. and tert-butyldimethylsilyl chloride (TBDMSCl) (1.33 g, 6.85 mmol) added over 5 minutes. After 18 h at room temperature, the volatiles were evaporated under reduced pressure and the residue purified by flash chromatography on silica gel with EtOAc:MeOH (95:5 to 90:10) to give the expected product (39) (2.10 g, 72%) together with unreacted starting material (490 mg). 1H NMR (d6 DMSO) δ 0.11 (s, 3H, CH3), 0.12 (s, 3H, CH3), 0.89 (s, 9H, 3CH3), 1.90 (ddd, J=13.2, 7.7 and 5.7 Hz, 1H, HH-2′), 2.18 (ddd, J=13.2, 5.7 and 2.3 Hz, 1H, HH-2′), 3.72 (dd, J=11.5, 3.6 Hz, 1H, HH-5′), 3.80 (dd, J=11.5, 2.8 Hz, 1H, HH-5′), 3.86-3.89 (m, 1H, H-4′), 4.14-4.18 (m, 1H, H-3′), 5.22 (1H, d, J=4.1 Hz, OH), 6.09 (1H, dd, J=7.8, 5.8 Hz, H-1′), 6.60 (br s, 1H, NHH), 7.81 (br s, 1H, NHH), 7.94 (s, 1H, H-6); MS (ES): m/z (%) (M+H) 468 (90%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6](OC)[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].O.P([O-])(O)(O)=[O:21].[Na+].P(=O)(O)(O)O.S(=O)(=O)(O)O>O.O1CCOCC1>[OH:21][CH:3]1[CH2:4][C:5](=[O:1])[C:6]([CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1
Reactant: O=P([O-])(O)O
Reactant: COC(=O)CCCC#CCC(OC)c1ccco1
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCC#CCC1=CC(O)CC1=O
Temperature: 50 °C
Yield: 72 %

Procedure:
A stirred solution of 25.0 g of methyl 8-(2-furyl)-8-methoxy-5-octynoate, 5.52 g of sodium dihydrogen phosphate monohydrate, 45.6 g of 86% phosphoric acid, 300 ml of dioxane and 200 ml of water was heated under reflux for 44 hours. The resulting solution, which contained a mixture of the 3- and 4-hydroxy isomers, was cooled to 50° C. and treated dropwise with 15 ml of concentrated sulfuric acid. This solution was stirred under reflux for 12 hours, cooled and partitioned with brine and ether. The organic layer was separated, washed with brine, dried and concentrated. The resulting oil was chromatographed on a silica gel column with chloroform progressively enriched in ether. The appropriate fractions were combined and concentrated, giving 6.4 g of the desired product which was recrystallized from ether, giving tan crystals, mp 65°-71° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:15])[CH2:13]I)[CH3:10]>CN(C=O)C.O>[CH2:9]([O:11][C:12](=[O:15])[CH2:13][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1)[CH3:10]
Reactant: CCOC(=O)CI
Reactant: Nc1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1cnc(N)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
61.1 To a stirred mixture of 2.8 g 3-amino-1,2,4-triazole in 50 ml DMF, 1.57 g NaH were slowly added at 0° C. under an argon atmosphere. After 1 hr stirring at 0° C., 3.31 ml ethyliodoacetate were added. The reaction mixture was stirred at r.t. over night. The mixture was diluted with water and extracted with EtOAc and CH2Cl2/MeOH 9:1. The organic phase was dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on silica, using a gradient from CH2Cl2 to CH2Cl2/MeOH 9:1 and then crystallization from cyclohexane/EtOAc to give 750 mg (3-amino-[1,2,4]triazol-1-yl)-acetic acid ethyl ester as a white solid.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:12]2)=O)=CC=1)([O-])=O.[OH-].[Na+]>CO>[OH:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:12]1
Reactant: COc1ccc(CCCN2CC[C@H](OC(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCCN2CC[C@H](O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-3-(4-Nitrobenzoyloxy)-1-[3-(4-methoxyphenyl)propyl]pyrrolidine (507 mg, 1.32 mmol) was dissolved in methanol (10 ml). 1 M-NaOH (1.5 ml) was added dropwise in the obtained mixture. After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure. The residue was distributed in water and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure to obtain (S)-3-hydroxy-1-[3-(4-methoxyphenyl)propyl] pyrrolidine in the form of a light yellow oil (310 mg, 100%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C.O>[NH2:12][C:10]([C:3]1[C:2]([F:1])=[C:7]([CH:6]=[CH:5][C:4]=1[F:9])[O:8][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(F)c(C(N)=O)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2,6-difluoro-3-hydroxybenzenecarboxamide (1.2 g, 7 mmol, 1 equiv.), K2CO3 (2.87 g, 21 mmol, 3 equiv.) and methyl bromoacetate (0.69 ml, 7.35 mmol, 1.05 equiv.) in DMF (30 ml) was stirred at r.t. for 18 h. The mixture was diluted with water and extracted with EtOAc (4×80 ml). The combined organic extracts were dried (MgSO4) and evaporated to dryness under reduced pressure. The product was used crude on the next step. HPLC-MS (method 1): m/z 246 [M+H]+, Rt=2.08 min.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.[CH:10]1([CH:13](O)[C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[NH:18][CH2:17]3)[CH2:12][CH2:11]1>O1CCOCC1>[CH:10]1([CH:13]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[NH:18][CH2:17]3)[CH2:11][CH2:12]1
Reactant: c1nc[nH]n1
Reactant: O=C1NCc2cc(C(O)C3CC3)ccc2N1
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: O=C1NCc2cc(C(C3CC3)n3cncn3)ccc2N1
Yield: 1.7 %

Procedure:
To a stirred and cooled (15° C.) solution of 2.5 parts of 1H-1,2,4-triazole in 70 parts of 1,4-dioxane was added dropwise 1 part of thionyl chloride under nitrogen atmosphere. After stirring for 10 minutes at 20° C., a solution of 2 parts of 6-(cyclopropylhydroxymethyl)-3,4-dihydro-2(1H)-quinazolinone in 80 parts of 1,4-dioxane was added portionwise to the previous mixture at 20°-25° C. After stirring overnight at room temperature, the precipitated product was filtered off, washed with 1,4-dioxane and purified by column chromatography over silica gel using a mixture of dichloromethane, methanol and methanol, saturated with ammonia (90:5:5 by volume) as eluent. The eluent of the desired fraction was evaporated and the residue was further purified, first by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (96:4 and 97.5:2.5 by volume) and then by column chromatography (RP 18) using a mixture of water and methanol (80:20 by volume) as eluents. The eluent of the desired fraction was evaporated and the residue was stirred in 2,2'-oxybispropane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 60° C., yielding 0.04 parts (1.7%) of 6-[cyclopropyl(1H-1,2-4-triazol-1-yl)methyl]-3,4-dihydro-2(1H)-quinazolinone; mp. 184.4° C. (comp. 25).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH3:13])=[C:7]2O.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]([CH3:12])[C:8]=1[CH3:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2c(Cl)cccc2c(O)c1C
Product: Cc1nc2c(Cl)cccc2c(Cl)c1C

Procedure:
Prepared according to procedure S using 8-chloro-2,3-dimethylquinolin-4-ol (1.14 g, 5.49 mmol) in POCl3 (7 mL). The resulting precipitate was collected by filtration to have 4,8-dichloro-2,3-dimethylquinoline. Mass Spectrum (ESI) m/e=227 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1.O1CCCC1.[Li]CCCC.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([C:2]2[CH:3]=[C:4]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[S:5][C:6]=2[C:7]2[NH:11][CH:10]=[N:9][N:8]=2)[OH:35])=[CH:32][CH:31]=1
Reactant: Brc1cc(-c2ccncc2)sc1-c1nnc[nH]1
Reactant: COc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc(-c3ccncc3)sc2-c2nnc[nH]2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a mixture of 4-[4-bromo-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (222.0 mg, 0.730 mmol) in tetrahydrofuran (5.9 mL, 72.3 mmol) cooled to −78° C. was added dropwise n-BuLi in hexanes (2.50 M, 1.2 mL, 2.90 mmol) under an atmosphere of argon and the mixture was stirred at −78° C. for 30 min. To the solution was added dropwise a solution of 4-methoxybenzaldehyde (0.53 mL, 4.34 mmol) in tetrahydrofuran (5.0 mL, 60 mmol) and the resulting solution was stirred for 30 min at −78° C. The reaction mixture was quenched by the addition of water (2 mL) and the resulting mixture was warmed to room temperature and stirred for 30 min. The mixture was extracted with EtOAc (5 mL) then the organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated under the reduced pressure. The obtained residue was purified by prep HPLC to yield 62.0 mg as a yellow solid (23.5%). LCMS: (FA) ES+ , 365. 1H NMR (400 MHz, d6-DMSO) δ: 8.68 (s, 1H), 8.55-8.57 (dd, J=1.5 Hz, 2H), 7.81 (s, br, 1H), 7.63-7.65 (dd, J=1.5 Hz, 2H), 7.40-7.44 (d, J=8.78 Hz, 2H), 6.82-6.84 (d, J=8.78 Hz, 2H), 6.72 (s, br, 1H), 3.68-3.69 (s, br, 3H).
Reaction SMILES: O[C@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1.CCN(S(F)(F)[F:31])CC>C(Cl)Cl>[F:31][C@@H:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[C@H:4]([CH3:24])[CH2:3]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@H](F)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: -20 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
tert-Butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.190 g, 3.558 mmol) was dissolved in methylene chloride (55 mL) and cooled to −20° C. The solution was treated with DAST (1.410 mL, 10.68 mmol) and stirred at −20° C. for 1 hour. The reaction was quenched with ice and then warmed to ambient temperature. The mixture was diluted with saturated NH4Cl and separated. The aqueous phase was extracted with methylene chloride (2×), and the combined organics were dried over Na2SO4 and concentrated to a dark oil. This oil was chromatographed on SiO2 (Biotage 40S, load with methylene chloride) then eluted with 2.5% MeOH/DCM then 3.5% MeOH/DCM. The mixed fractions were concentrated, and the material was re-chromatographed on SiO2 (Biotage 40S, load with DCM) and eluted with 2 hexane/EtOAc. The product was collected as a dark oil to give tert-butyl 4-((5R,7S)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.725 g, 61%). LCMS (APCI+) m/z 337.0 [M+H]+; Rf 3.13 min.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:14][CH:15]=1)[O:8][CH2:9][CH2:10][C:11]2=[O:13])([O-:3])=[O:2]
Reactant: O=C(O)CCOc1ccc([N+](=O)[O-])cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Product: O=C1CCOc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of 3-(4-nitrophenoxy)propanoic acid (6.5 g, 30 mmol), concentrated sulfuric acid (30 mL) and phosphorus pentoxide (5.2 g, 37 mmol) is stirred at 60° C. for 3 hours, poured onto ice, stirred for 15 minutes and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a beige solid, 5.5 g (94% yield) mp 171-173° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH:1]1([C@@H:4]([OH:18])[CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[O:16][CH3:17])[CH2:3][CH2:2]1>CCO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C@@H:4]([CH:1]2[CH2:2][CH2:3]2)[OH:18])=[C:8]([O:16][CH3:17])[CH:9]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OC[C@H](O)C1CC1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1OC[C@H](O)C1CC1

Procedure:
To a solution of (R)-1-cyclopropyl-2-(2-methoxy-4-nitrophenoxy)ethanol (20.90 g, 83 mmol), prepared in Part C, in EtOH (546 ml) was added 5% Pd/C, dry basis, Degussa type 50% water content (3.0 g, 0.705 mmol). The suspension was hydrogenated (1 atm. H2, balloon) at 20° C. for 2.5 h; whereupon, LC/MS analysis revealed the reaction to be complete. After filtration of the reaction mixture through CELITE® pad and subsequent washing of the cake with EtOH, the filtrate was concentrated under vacuum using a rotary evaporator to yield (R)-2-(4-amino-2-methoxyphenoxy)-1-cyclopropylethanol as a brown solid. M.P. 71° C. (18.34 g, 100%). 1H NMR (400 MHz, CDCl3): δ 0.18-0.27 (m, 1H), 0.38-0.43 (m, 1H), 0.45-0.61 (m, 2H), 0.82-0.92 (m, 1H), 3.21 (ddd, J=8.8, 8.8, 2.6 Hz, 1H), 3.80 (s, 3H), 3.86 (dd, J=10.1, 8.8 Hz, 1H), 4.09 (dd, J=10.1, 2.6 Hz, 1H), 6.21 (dd, J=8.3, 2.7 Hz, 1H), 6.29 (d, J=2.7 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 151.2, 142.1, 140.8, 118.7, 106.9, 100.5, 76.5, 74.4, 55.7, 12.9, 2.5, 1.6. HPLC: 6.28 min retention time, 98.5% API; ZORBAX® column SB C18 4.6×75 mm; flow rate 2.5 ml/min; Gradient solvent system: from 100% A:0% B to 0% A:100% B for 8 min (Solvent A: 10% MeOH 90% H2O=0.2% H3PO4; Solvent B: 90% MeOH−10% H2O+0.2% H3PO4) Detection at 220 nm. LC/MS: m/e 224.5 (M+H); 4 min gradient.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:6]1[CH2:5][C@@H:4]([CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1)[NH:3][CH2:2]2.[CH2:20]([O:22][C:23]1[C:24]([C:30](O)=[O:31])=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[C:24]([C:30]([N:3]2[C@H:4]([CH2:8][NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:12][N:11]=3)[CH2:5][C@H:6]3[C@H:1]([CH2:7]3)[CH2:2]2)=[O:31])=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=1)[CH3:21]
Reactant: CCOc1ccc(C)nc1C(=O)O
Reactant: FC(F)(F)c1ccc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)nc1
Product: CCOc1ccc(C)nc1C(=O)N1C[C@H]2C[C@H]2C[C@H]1CNc1ccc(C(F)(F)F)cn1
Yield: 92 %

Procedure:
Following a similar procedure to that described for Example 1, N-[(1S,4S,6S)-3-azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyridinamine D12 (0.030 g) and 3-(ethyloxy)-6-methyl-2-pyridinecarboxylic acid D15 (0.020 g) were reacted to give the free base of the title compound (0.044 g, 0.101 mmol, 92% yield). HPLC (walk-up): rt=4.14 min. MS: m/z (ES/+): 435 (M+1). C22H25F3N4O2 requires 434. 1H NMR [the SYN relative stereochemistry is derived from the stereochemistry of the previous intermediate D8. The product is present as a mixture of conformers. The assignment is provided for the major component] (400 MHz, DMSO-d6) δ ppm: 8.26 (m, 1 H), 7.72-7.56 (m, 1 H), 7.18-7.47 (m, 3H), 6.83-6.61 (m, 1 H), 4.24-4.10 (m, 1 H), 4.10-3.88 (m, 2 H), 3.67-3.34 (m, 3 H), 2.67-2.56 (m, 1 H), 2.43-2.37 (s, 3 H), 2.43-2.34 (m, 1 H), 1.23-1.19 (m, 3 H), 1.20-0.8 (m, 3 H), 0.72-0.58 (m, 1 H), 0.15-0.24 (m, 1 H).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.Br[CH2:16][Cl:17]>>[Cl:17][CH2:16][S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: Cn1ccnc1S
Reactant: ClCBr
Solvent: CCN(CC)CC
Product: Cn1ccnc1SCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (40 mmol) was added to a mixture of 2-mercapto-1-methylimidazole (40 mmol) and bromochloromethane (0.8 mol). The mixture was stirred for 1 hour at room temperature, washed with water and the dried (MgSO4) solution evaporated. Yield: 5.85 g (90%). 1H NMR (CDCl3, δ): 3.77 (CH3), 5.00 (CH2), 6.7-7.2 (H-4 and H-5). The product was used in the succeeding step without further purification.