Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:29]>C1C=CC=CC=1.CN(C)C=O>[CH3:1]/[C:2](/[CH:7]=[CH:8]/[C:9](/[F:22])=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16]([CH3:19])[S:15][C:14]=1[CH3:20])=[CH:3]\[C:4]([NH2:29])=[O:5]
Reactant: N
Reactant: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(N)=O

Procedure:
A suspension of 0.40 g. (0.12 mmol) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid in 12 ml. of dry benzene was stirred at 23° C. under argon while about 5 mg. of dimethylformamide were added thereto followed by 0.24 g. (0.19 mmole) of oxalyl chloride in 3 ml. of dry benzene. After 1 hour of stirring dry ammonia was bubbled into the resulting orange solution until a bright yellow color persisted. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried with magnesium sulfate, filtered, and evaporated to give a crude orange solid. This material was purified by chromatography on silica gel using ethyl acetate-hexane (2:3 parts by volume) as the elutant. One crystallization from ethyl acetate gave 70 mg. (18% yield) of pure 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenamide, m.p. 212°-215° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:11])=[N:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:26](=[O:33])[CH:27]=[C:28]([CH2:31][OH:32])[O:29][CH:30]=1.O>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O:11][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]2[C:26](=[O:33])[CH:27]=[C:28]([CH2:31][OH:32])[O:29][CH:30]=2)=[N:3][CH:2]=1
Reactant: Oc1ncnc2ccccc12
Reactant: O=c1cc(CO)occ1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCOc1ncnc2ccccc12
Reaction time: 0.17 h
Yield: 26 %

Procedure:
Quinazolin-4-ol (1.0 g, 6.84 mmol) was dissolved in DMF (7 mL). Cs2CO3 (2.23 g, 6.84 mmol) was added at RT and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (1.90 g, 6.52 mmol) in DMF (7 mL) was added via syringe. This mixture was stirred at 50° C. for 2 h. Water (150 mL) was added and the mixture extracted with EtOAc (2×100 mL), washed with water (3×100 mL), brine (3×100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:5. 5-(5-(Quinazolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 15 was obtained (0.61 g, 26% yield) as a pale yellow solid.
Reaction SMILES: [C:1]([CH2:9][C:10]([O-:12])=O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:13][NH:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[CH3:13][N:14]1[C:1]([C:2]2[CH:3]=[CH:4][N:5]=[CH:6][CH:7]=2)=[CH:9][C:10](=[O:12])[N:15]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])CC(=O)c1ccncc1
Reactant: CNNc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(-c2ccncc2)cc(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
thyl isonicotinoylacetate (3.01 g, 16 mmol) and 1-methyl-2-phenylhydrazine (2.03 g, 17 mmol) were suspended in water (50 ml) and glacial acetic acid (1.35 ml, 23 mmol) was added. The flask was fitted with a reflux condenser and placed in a preheated oil bath (115 C) and stirred. After 4 hours, the reaction cooled to room temperature and extracted with EtOAc (2×100 ml; 50 ml), 10:1 DCM/MeOH (110 ml), and EtOAc again. The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude material was purified on silica gel (DCM->20:1->10:1 DCM/MeOH->10:1->4:1 DCM/2 N ammonia in MeOH). Fractions with product collected, concentrated, and repurified on silica gel using DCM->20:1 DCM/MeOH->5:1 DCM/2 N ammonia in MeOH). The fractions with product were collected and concentrated to give 1-methyl-2-phenyl-5-(pyridin-4-yl)-1,2-dihydropyrazol-3-one (3.31 g, 70% purity, 9.2 mmol, 59%). MS (ESI pos. ion) m/z: 252 (MH+). Calc'd exact mass for C15H13N3O: 251.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[NH2:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: Cc1cccc(-c2sc(N)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(N)nc2C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-amino-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.24 min; [M+H]+=493.1.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][C:33]([F:32])([F:44])[F:45])[CH:36]=3)[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(OC(F)(F)F)c1)N1CCN(C2CCC2)CC1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-(trifluoromethoxy)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown foam (61%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([C:16]#[N:17])=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[N:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[CH3:32])[CH2:27][NH2:28]>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:18]2[O:19][CH2:20][CH2:21][CH:22]=2)[C:5]([C:16]#[N:17])=[C:6]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:24]([CH3:23])[CH:25]=2)[N:7]=1
Reactant: Cc1ccc(CN)cc1C
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1C1=CCCO1
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(C3=CCCO3)c2C#N)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.7 %

Procedure:
To a stirred suspension of 250 mg (0.74 mmol) trifluoromethanesulfonic acid 2-amino-5-cyano-6-(4,5-dihydro-furan-2-yl)-pyrimidin-4-yl ester in 10 ml DME was added 0.20 g (1.49 mmol) 3,4-dimethylbenzylamine and the mixture stirred at room temperature for 1 hour. The reaction mixture was then partitioned between water and ethyl acetate and the organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether/hexane afforded 35 mg (15%) 2-amino-4-(4,5-dihydro-furan-2-yl)-6-(3,4-dimethyl-benzylamino)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[CH:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([OH:14])([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:24])[CH:3]=2)=[CH:27][C:26]=1[Cl:25])=[O:33]
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Reactant: COc1ccc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)cn1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc(OC)nc3)C(F)(F)F)c(Cl)c2)cc1Cl

Procedure:
In analogy to Example 150, step 2, 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(6-methoxy-pyridin-3-yl)-butan-2-ol (Example 175, step 3) was reacted with 3-chloro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless foam. MS (m/e)=514.4 [M+H+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[CH:18]1([CH2:17][S:15][C:13]2[O:14][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)=[N:11][N:12]=2)[CH2:20][CH2:19]1
Reactant: ClCC1CC1
Reactant: Sc1nnc(-c2ccc3c(c2)CCO3)o1
Product: c1cc2c(cc1-c1nnc(SCC3CC3)o1)CCO2
Yield: 56 %

Procedure:
In the same manner as in Example 1 and using 5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and (chloromethyl)cyclopropane instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 56%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:1][C:2]2[CH:7]=[C:6]([C@:8]3([CH3:20])[C:14]([F:15])([F:16])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]3)[C:5]([F:21])=[CH:4][C:3]=2[F:22])=[O:32])=[N:29][CH:30]=1)#[N:24]
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)c(F)cc2F)C1(F)F
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC(=O)c3ccc(C#N)cn3)c(F)cc2F)C1(F)F
Yield: 82 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (R)-5-(5-amino-2,4-difluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17C) (70 mg, 0.208 mmol) and commercially available 5-cyano-pyridine-2-carboxylic acid [CAS No. 53234-55-2] (46 mg, 0.312 mmol). The compound was obtained as a light yellow foam (80 mg, 82%). MS (ISP): m/z=467.1 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2.Br[CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:31][C:32]#[N:33])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][NH:14][C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH2:27][CH2:28][CH3:29])=[O:16])=[CH:7]2
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (300 mg, 0.66 mmol), prepared in the previous step, bromoacetonitrile (56 μL, 0.80 mmol) and potassium carbonate (460 mg, 3.32 mmol) in 15 mL of DMF was stirred under nitrogen at room temperature for 18 h (overnight). The reaction was diluted with ethyl acetate, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (324 mg, 99%) as an off-white solid, mp154-157° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[S:25][CH:29]=[CH:28][N:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: c1cscn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1)c1nccs1

Procedure:
This compound is prepared by method C using compound 12e and thiazole
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-:21].[K+].Cl>C(O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)c(Cl)c2)c1C#N
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1

Procedure:
Fifteen g. of ethyl 1-(3,4-dichlorophenyl)-5-cyano-4-pyrazolecarboxylate was dissolved in 200 ml. of ethanol, and 5.6 g. of potassium hydroxide wasadded. The reaction mixture was stirred under reflux for 1 hour, and was then poured over a large amount of ice and made acid with concentrated hydrochloric acid. The mixture was filtered, and the solids were found by nuclear magnetic resonance analysis to consist of the partially hydrolyzed4-carboxy-5-cyanopyrazole. A 2 g. portion of that intermediate was held outfor further examination, and the rest of the solids were redissolved in 200ml. of ethanol and stirred under reflux for 18 hours with 5.6 g. of potassium hydroxide. The mixture was then poured over ice, made acid, and filtered. The solids were recrystallized from ethanol, and the mother liquor was chromatographed over a silica gel column with methanol as the eluent. The product-containing fractions were evaporated to dryness and the residues were recrystallized from methanol to obtain the desired product, m.p. 249°-250°. The elemental analysis was as follows.
Reaction SMILES: C(N(CC)CC)C.[OH:8]/[N:9]=[C:10](\[NH2:20])/[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>ClCCl>[OH:8]/[N:9]=[C:10](\[NH:20][C:22](=[O:23])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[C:14]([CH3:19])[CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(C/C(N)=N/O)ccc1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C/C(=N/O)NC(=O)Oc2ccccc2)ccc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
Triethylamine (0.651 mL, 4.67 mmol) was added to (Z)—N′-hydroxy-2-(4-iodo-3-methylphenyl)acetimidamide (Intermediate 29-3; 1.13 g, 3.90 mmol) in dry dichloromethane (30 mL) at 0° C. The resulting yellow solution was stirred at 0° C. for 1 hour. Phenyl chloroformate (0.598 mL, 4.67 mmol) was added and the reaction mixture stirred at 0° C. for a further 1 hour. The solution was washed sequentially with saturated Na2CO3 (50 mL) and water (50 mL×2). The organic layer was dried over MgSO4, filtered and evaporated to afford (Z)-phenyl 1-(hydroxyimino)-2-(4-iodo-3-methylphenyl)ethylcarbamate (1.675 g, 105%) as crude product.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[O:9]=[C:10]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.O>CS(C)=O>[O:31]1[C:28]2([CH2:27][CH2:26][N:25]([C:10](=[O:9])[CH2:11][N:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[CH2:30][CH2:29]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC(=O)CC2)CC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)CO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Trimethylsulfoxonium iodide (2.02 g, 9.20 mmol) was gradually added to a suspension of sodium hydride (385 mg, 9.64 mmol) in dimethylsulfoxide (50 ml), and the resultant mixture was stirred at room temperature for 1 hour. To which tert-butyl 4-[2-oxo-2-(4-oxopiperidin-1-yl)ethyl]piperazine-1-carboxylate (2.85 g, 8.76 mmol) in DMSO (10 ml) was added, and the mixture was stirred at room temperature for 2 hours, and stirred at 55° C. for 1 hour. The reaction mixture was poured into iced water, and extracted with diethyl ether. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate, and filtered. The resultant filtrate was concentrated under a reduced pressure to afford tert-butyl 4-[2-(1-oxa-6-azaspiro[2,5]octan-6-yl)-2-oxoethyl]piperazine-1-carboxylate (2.97 g, yield 99%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc(F)cc1
Yield: 7.6 %

Procedure:
A solution of 5-chloropyrimidin-2-one (1.309 g) and 2-chloro-4'-fluoroacetophenone (1.726 g) in triethylamine (2 ml) and ethanol (50 ml) was stirred and heated at reflux for 11/2 hours. After evaporation of solvents, the residue was triturated with water (100 ml). The resulting collected solid was crystallised from ethanol then acetone, but still required purification, by preparative thin-layer chromatography on silica developed in chloroform-ethanol (25:1 v/v), before crystallisation from propan-2-ol to give the title pyrimidinone (204 mg,); 196°-202°; λmaxEtOH 245 nm (ε 17780), 333 nm (ε 2090), λinf 236 nm (ε 15230), 280 nm (ε 980).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[N+:8]=[N-:9])=[CH:3][CH:2]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>CCO>[NH2:12][C:11]1[N:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[N:8]=[N:9][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2ccc(C)cc2)c1N
Yield: 73.5 %

Procedure:
Reaction of p-tolyl azide (9.38 g; 0.0705 mole) with ethyl cyanoacetate (7.96 g: 0.0705 mole) as described in example 1a gave 12.76 g (74%) of the triazole of mp (EtOH) 152-153° C. (lit mp 147.5° C., B. R. Brown, D. L. Hammick and S. G. Heritage J. Chem. Soc. 3870 [1953]). (Found; C, 58.38; H 5.90; N, 22.89; C12H14N4O2 requires; C, 58.52; H, 5.73; N, 22.75%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]=[CH:12][CH2:13][OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>ClCCl>[CH3:20][C:21]([Si:24]([CH3:26])([CH3:25])[O:14][CH2:13][CH:12]=[CH:11][S:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)([CH3:23])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(SC=CCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC=CSc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.8 %

Procedure:
A solution of a 1.5 to 1 mixture of (E) and (Z) 3-(4-nitrophenylthio)-2-propenol (3.53 g, 16.71 mmol) (JCS, Perkin Trans. I, 1974, 25) in dichloromethane (40 mL) was treated with imidazole (2.28 g, 33.4 mmol) and TBDMSCl (2.77 g, 18.4 mmol), stirred at room temperature for 24 hours, and then partioned between dichloromethane and water. The organic phase was dried, concentrated, and purified on silica gel by flash column chromatography eluting with 8 to 1 hexanes/ethyl acetate to give 5.1 g (94%) of the desired product. Rf: 0.8 (2:1 hexane:ethyl acetate)
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14][C:15](=[O:17])[CH3:16])([O-:3])=[O:2].[C:18]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:18][N:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:4]=1[N+:1]([O-:3])=[O:2])[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc(C(F)(F)F)c1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p. 107) (2.0 g) was dissolved in DMF (15 ml) prior to the addition of K2CO3 (2.07 g) and MeI (0.71 ml). After 2 h, the solution was concentrated and 1N HCl solution (aq) was added. The solution was extracted with EtOAc. The organic layer was washed with brine, dried, filtered, and concentrated. Filtration through a plug of silica of the resulting residue gave N-methyl-N-(2-nitro-3-trifluoromethyl-phenyl)-acetamide. This material (2 g) was dissolved in EtOH prior to the addition of a solution of NaOH (2 g) in H2O (2 ml). The mixture was heated to reflux for 2 h, cooled to rt, and neutralized with 1N HCl, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was dissolved in MeOH (50 ml) prior to the addition of 10% Pd/C (2.07 g). This solution was placed on a Parr apparatus under H2 (50 psi) for 2 h. The Pd/C was filtered off and the solution was concentrated. The resulting residue was dissolved in diethyl malonate. The reaction was heated at 160° C. oil bath for 45 min. After cooling to rt, flash chromatography of the crude reaction gave (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid ethyl ester (1.05 g). A portion (200 mg) of this material was dissolved in THF (17 ml) prior to the addition of a solution of LiOH (31 mg) in H2O (6 ml). MeOH (6 ml) was added. After 2 h at rt, the reaction was concentrated and freeze-dried to provide (1-methyl-4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt (189 mg). MS found: (M+H)+=259.2
Reaction SMILES: [CH:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)=[CH:5][CH:4]=1)=[O:2].[CH3:38][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)=[CH:36][CH:37]=1)[CH3:38]
Reactant: C[Mg]Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C=O)cc2)c2ncnn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(C(C)O)cc2)c2ncnn12
Temperature: 0 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
4′-{[4-(4-Formylbenzyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.3 g) was dissolved in tetrahydrofuran (30 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 2.8 mL) was added at −78° C. The reaction mixture was warmed to 0° C., and stirred for 6 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.2 g, 90%).