Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.C(ON=O)(C)(C)C>O1CCCC1>[C:19]([C:4]1[C:3]([C:21]2[CH:25]=[CH:24][O:23][CH:22]=2)=[CH:2][N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=1)#[N:20]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1ccoc1
Temperature: 65 °C

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.204 g) in tetrahydrofuran (3 ml) was added t-butylnitrite (187.8 μl). The mixture was heated to 65° C. for 1 hour, then cooled and evaporated. The residue was purified by column chromatography on silica gel (5 g) eluted with hexane containing increasing amounts of dichloromethane (up to 100%). Combination and evaporation of appropriate fraction gave the title compound as a white solid, m.p. 139° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=O)[O:8][CH:7]=1)=[O:5])[CH3:2].[CH2:13]([NH:16][CH2:17][CH:18]=[CH2:19])[CH:14]=[CH2:15].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][N:16]([CH2:17][CH:18]=[CH2:19])[CH2:13][CH:14]=[CH2:15])[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc(C=O)c1
Reactant: C=CCNCC=C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: C=CCN(CC=C)Cc1cc(C(=O)OCC)co1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of 5-formyl-3-furancarboxylic acid ethyl ester (prepared as described in Tetrahedron (1996), 52(12), 4245-56) (1.61 g) in dichloromethane (20 ml) was added diallylamine (1.18 ml). The solution was treated with glacial acetic acid (0.55 ml) and then sodium triacetoxyborohydride (4.2 g). The suspension was stirred at room temperature for 3.5 h. The suspension was treated with ethanol (80 ml) and stirred at room temperature for 25 mins. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The phases were separated and the organic phase washed with saturated aqueous sodium hydrogen carbonate (100 ml) and brine (50 ml). The combined aqueous phases were extracted with ethyl acetate (50 ml). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo. The residue was dissolved in methanol and applied equally onto SCX sulphonic acid ion exchange cartridges (10 g×4, pre-treated with methanol). The cartridges were eluted with methanol followed by 10% 0.880 ammonia in methanol; evaporation of the basic fractions in vacuo gave the title compound as a mobile oil (2.06 g).
Reaction SMILES: [CH2:1]([C:4]1([OH:9])[CH2:7][CH:6]([CH3:8])[CH2:5]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.O([Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])S(C(F)(F)F)(=O)=O.O>C(Cl)Cl>[CH2:1]([C:4]1([O:9][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:7][CH:6]([CH3:8])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(O)CC(C)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC1(O[Si](C)(C)C(C)(C)C)CC(C)C1

Procedure:
1-Allyl-3-methylcyclobutanol (2.25000 g, 17.8 mmol) (the 4:1 mixture of cis/trans-isomers) was dissolved in 50 ml of CH2Cl2 and DIEA (5.59 ml, 32.1 mmol) and tert-butyldimethylsilyl triflate (5.73 ml, 25.0 mmol) were added. The mixture was stirred for 2 h and hydrolyzed with water, extracted with 200 ml Et2O (3× each), dried over MgSO4 and evaporated. Glass col. chrom. (10-30% EtOAc in Hex.) provided (1-allyl-3-methylcyclobutoxy)(tert-butyl)dimethylsilane as a yellow oil. Mixture of cis/trans at the cyclobutylring (4:1)
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[C:2]1=[O:3])[CH2:4][CH2:6][CH3:7]
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccccc21
Yield: 65.3 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 5 and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 65.3%. 1H NMR (DMSO-d6): δ 0.95 (t, J=7.5 Hz, 3H), 1.36-1.41 (m, 2H), 1.64-1.69 (m, 2H), 3.78 (t, J=7.2 Hz, 2H), 7.19 (t, Hz, J=7.5 Hz, 1H), 7.24 (d, J=7.8 Hz, 1H), 7.49 (td, J=1.2 Hz, J=7.8 Hz, 1H), 7.60-7.73 (m, 4H), 7.90-7.92 (m, 2H), 13.90 (br, s 1H). 13C NMR (DMSO-d6): δ 14.06 (CH3), 20.04 (CH2), 29.56 (CH2), 39.49 (CH2), 110.69 (CH), 119.66 (C), 121.26 (CH), 123.69 (CH), 127.88 (CH), 129.67 (CH), 132.22 (CH), 132.43 (C), 133.40 (CH), 137.40 (C), 143.43 (C═N), 161.58 (C═O), 163.34 (C═O). HRMS (ES+) calcd for C19H20N3O2 (M+H+), m/e, 322.1548; found, 322.1550.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].O1CCCC1.[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1.[CH2:20]([O:22][C:23]([C:25]1[C:34](=[O:35])[N:33]2[C:28]([C:29]([SH:36])=[CH:30][CH:31]=[CH:32]2)=[CH:27][CH:26]=1)=[O:24])[CH3:21]>C(N(CC)CC)C>[CH2:20]([O:22][C:23]([C:25]1[C:34](=[O:35])[N:33]2[C:28]([C:29]([S:36][C:2]([N:14]3[CH2:19][CH2:18][S:17][CH2:16][CH2:15]3)=[O:3])=[CH:30][CH:31]=[CH:32]2)=[CH:27][CH:26]=1)=[O:24])[CH3:21]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2c(S)cccn2c1=O
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(SC(=O)N3CCSCC3)cccn2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
A mixture of 0.24 ml of trichloromethyl chloroformate (TCF) and 15 ml of tetrahydrofuran is stirred at 60° C. for 2 hours, cooled with ice, mixed with 412 mg of thiomorpholine, and the mixture is stirred for 1 hour at room temperature. The reaction mixture is cooled with ice again and mixed with 1.212 g of triethylamine. The mixture is stirred at room temperature for 1 hour, mixed with 500 mg of 3-ethoxycarbonyl-9-mercapto-4H-quinolizin-4-one (II-3), and the mixture is stirred at room temperature for 17 hours. The reaction mixture is filtered, and the filtrate is concentrated. The residue is chromatographed on a column of 10 g of silica gel, eluting with methylene chloride-methanol (19:1 v/v). The resultant crystals are recrystallized from ethyl acetate to give 321 mg (Yield: 42.3%) of 3-ethoxycarbonyl-9-(thiomorpholinocarbonylthio)-4H-quinolizin-4-one (I a-6).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:8]=C(C#N)[C:6]=1[O:17][CH3:18])C.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>>[C:11]([C:9]1[N:8]=[C:23]([C:22]([OH:20])=[O:24])[C:6]([O:17][CH3:18])=[C:5]([C:4]([OH:3])=[O:19])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCO
Reactant: [OH-]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nc(C#N)c1OC
Agent: [Na+]
Product: COc1c(C(=O)O)cc(C(C)(C)C)nc1C(=O)O
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of the above nitrile (616 mg, 2.35 mmol) in ethanol (8.0 mL) was added NaOH (2.0 M in water, 8.3 mL, 16.5 mmol). The mixture was heated to reflux for 20 h then cooled to room temperature and the ethanol was concentrated in vacuo. The basic solution was neutralized with 12 N HCl to a pH=6 then extracted with chloroform/isopropanol (3:1). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide 6-tert-butyl-3-methoxy-pyridine-2,4-dicarboxylic acid (402 mg, 68%) as a yellow solid which was utilized without further purification.
Reaction SMILES: [NH3:1].Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:4]=1>CO>[NH2:1][C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:18]=[C:17]3[C:13]([CH:14]=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH:4]=1
Reactant: N
Reactant: Clc1cc(Nc2ccc3cc[nH]c3c2)ncn1
Solvent: CO
Product: Nc1cc(Nc2ccc3cc[nH]c3c2)ncn1
Temperature: 130 °C
Yield: 78 %

Procedure:
A 7N ammonia in methanol solution (75 ml) was added to 6-chloro-4-(1H-6-indolylamino)pyrimidine (1.229 g, 5.0 mmol); and the reaction mixture was heated in a sealed tube at 130° C. for 6 days. The solvent was distilled off under reduced pressure; the residue was purified by silica gel column chromatography (eluent; ethyl acetate:tetrahydrofuran=1:1); diethyl ether was added to the residue to crystallize; the crystals were filtered off, and washed with diethyl ether, and dried under aeration to yield the title compound (883 mg, 3.9 mmol, 78%) as pale yellow crystals.
Reaction SMILES: C([CH:3]1[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=2)[C:6](=[O:16])[C:5]2[N:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:18]=[C:19]([C:20]([NH2:22])=[O:21])[C:4]1=2)C.C(OC([N:41]1[CH2:46][CH2:45][NH:44][C:43](=[O:47])[CH2:42]1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>CCOC(C)=O.O.[Cu]I>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([N:17]2[C:5]3[C:6](=[O:16])[N:7]([C:9]4[CH:10]=[CH:11][C:12]([N:44]5[CH2:45][CH2:46][NH:41][CH2:42][C:43]5=[O:47])=[CH:13][CH:14]=4)[CH2:8][CH2:3][C:4]=3[C:19]([C:20]([NH2:22])=[O:21])=[N:18]2)=[CH:28][CH:27]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CCC1CN(c2ccc(I)cc2)C(=O)c2c1c(C(N)=O)nn2-c1ccc(OC)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(N4CCNCC4=O)cc2)CC3)cc1
Temperature: 130 °C
Yield: 43.4 %

Procedure:
Part A. To ethyl-6-(4-iodophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo(3,4-c)pyridine-3-carboxamide (0.52 g, 1.0 mmol), 4-benzyloxycarbonylpiperazin-2-one (0.32 g, 1.4 mmol), and K2CO3 (0.22 g, 1.6 mmol) was added DMSO (5 mL). The mixture was degassed with N2. CuI (38 mg, 0.2 mmol) was added and the reaction was heated to 130° C. for 18 h. The reaction was diluted with EtOAc and water, extracted with EtOAc, and dried (MgSO4). Purification by chromatography on silica gel using 5% MeOH/CH2Cl2 afforded 0.2 g (33%) of a foam; Mass Spec (M+H)+ 624.6.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:3]1=[O:31].[Li+].CC([N-]C(C)C)C.[CH3:40][CH:41]([CH3:45])[CH2:42][CH:43]=[O:44]>C1COCC1.C(Cl)Cl.O>[OH:44][CH:43]([C:11]1[C:6]2[C:5](=[O:20])[N:4]([CH2:21][CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:3](=[O:31])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)[CH2:42][CH:41]([CH3:45])[CH3:40]
Reactant: Cc1cncc(Oc2cnc3c(c2)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cncc(Oc2cnc3c(c2C(O)CC(C)C)c(=O)n(CCCOC2CCCCO2)c(=O)n3C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy) propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 27, step 1, 100 mg, 0.23 mmol) in THF (5 mL) at −78° C. was added LDA (2M in THF, 0.48 mL, 0.940 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (40 mg, 0.470 mmol) in THF (1 mL) was added. The reaction was stirred at −78° C. for 45 min then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to give 5-(1-hydroxy-3-methylbutyl)-1-methyl-6-(5-methylpyridin-3-yloxy)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (120 mg, 90% yield) as a solid. LCMS: [M+-THP] 429 and TR=1.769 min. Used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9](C)=[CH:10][CH:11]=[C:6]2[N:5]=[C:4]1O)[CH3:2].[OH:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.[CH2:48](P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[N:5]=[C:4]1[CH2:48][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:21]2=[O:45])=[CH:46][CH:47]=1)[CH3:2]
Reactant: CCCCP(CCCC)CCCC
Reactant: CCn1c(O)nc2ccc(C)nc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.5 g of 3-ethyl-2-hydroxy-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 28), 1.313 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.77 ml of tributylphosphine, 0.712 g of 1,1'-(azodicarbonyl)di-piperidine and 80 ml of benzene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 300 mg of the title compound having Rf=0.55 (on silica gel thin layer chromatography using a 1:3 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.[CH:41](=O)[CH3:42].CO.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:47].[Na+]>C1COCC1>[CH2:46]([N:1]([CH2:41][CH3:42])[C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:36])([F:37])[F:38])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1)[CH3:47]
Reactant: CC=O
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (82 mg) and acetaldehyde (32 mg) in THF (0.24 mL)/methanol (0.48 mL) was added sodium triacetoxyborohydride (154 mg), and the mixture was stirred at 0° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (34 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[CH2:18]([O:25][CH2:26][C@H:27]([OH:30])[CH2:28]O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][C@H:27]([OH:30])[CH2:26][O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: OC[C@@H](O)COCc1ccccc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OC[C@H](O)COCc3ccccc3)ccc2c1

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 3.70 g, 16.1 mmol), (R)-(+)-3-benzyloxy-1,2-propanediol (2.92 g, 19.0 mmol), N,N-dimethylaminopyridine (DMAP, 0.40 g, 3.3 mmol) and 1,3-dicyclohexylcarbodiimide (3.61 g, 17.5 mmol) in CH2Cl2 (120 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The reaction mixture was partitioned between HCl (3N, 50 mL) and CH2Cl2 (50 mL×2). The combined organic extracts were back washed with water, brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with EtOAc:hexane (1:2, Rf=0.23) to give a mixture of the 1- and 2-glycerol ester isomers (88:12, 3.87 g). 1H NMR (300 MHz, CDCl3) δ 7.69-7.64 (m, 3H), 7.40-7.03 (m, 8H), 5.34 (s, 2H), 4.17-4.14 (m, 2H), 3.88 (s, 3H), 3.9-3.85 (m, 2H), 3.33-3.28 (m, 2H), 2.45 (br. d, 1H), 1.56 (d, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ174.6, 157.6, 137.6, 135.4, 133.6, 129.6, 129.2, 128.8, 128.3, 127.7, 127.61, 127.55, 127.1, 126.1, 125.9, 119.0, 105.5, 73.3, 70.6, 68.8, 65.5, 62.2, 55.2, 45.3, 18.3. Mass spectrum (API-TIS) m/z 412 (M+NH4)+.
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[C:10]([F:16])[CH:9]=1.[CH3:17][O:18][C:19]1[C:24](C)=[CH:23][C:22]([N:26]2[C:31](=[O:32])[N:30](CC3C(F)=CC(F)=CC=3F)[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27]2(=[O:48])=[O:47])=[CH:21][C:20]=1C>CN(C=O)C>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:30]2[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27](=[O:47])(=[O:48])[N:26]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[C:24]([O:2][CH3:1])[CH:23]=3)[C:31]2=[O:32])=[C:10]([F:16])[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(Cl)ccc1CBr
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3ccc(Cl)cc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (43 mg, 0.09 mmol) was prepared from (IntA1) (50 mg, 0.15 mmol), K2CO3 (62 mg, 0.45 mmol) and 4-chloro-2-fluorobenzyl bromide (40 mg, 0.18 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].C[N:22](C=O)C>C(OCC)(=O)C.O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][C:5]2[N:15]=[N:16][NH:17][N:22]=2)=[CH:8][CH:9]=1.[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][C:5]2[N:15]=[N:16][NH:17][CH:6]=2)=[CH:12][CH:11]=1
Reactant: C#CCCCCc1ccc(OC)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCCCc2c[nH]nn2)cc1
Product: COc1ccc(CCCCc2nn[nH]n2)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.80 g (9.56 mmol) 1-hex-5-ynyl-4-methoxy-benzene, 1.86 g (28.6 mmol) sodium azide, 1.53 g (28.6 mmol) ammonium chloride and 80 ml DMF was kept at 125° C. for 7 d with an extra addition of 1.80 g sodium azide and 1.53 g ammonium chloride every day. After cooling to r.t. the dark reaction mixture was distributed between water and ethyl acetate. The organic phase was dried over sodium sulphate and the solvent distilled off. The residue was separated by HPLC on a RP18-endcapped column (methanol/water) (a reversed phase column which is used with methanol/water as eluent) to yield 450 mg 5-(4-(4-Methoxy-phenyl)-butyl)-2H-tetrazole and 500 mg 4-(4-(4-Methoxy-phenyl)-butyl)-1H-[1,2,3]triazole
Reaction SMILES: [NH2:1][OH:2].Cl.NO.C[O-].[Na+].[N+:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH:14]=[CH:15][C:16]#[N:17])([O-:11])=[O:10]>CO>[N+:9]([C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH:14]=[CH:15][C:16](=[N:1][OH:2])[NH2:17])([O-:11])=[O:10]
Reactant: NO
Reactant: N#CC=Cc1ccccc1[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(C=Cc1ccccc1[N+](=O)[O-])=NO

Procedure:
A solution of hydroxylamine prepared from hydroxylamine hydrochloride (8.34 g.) in methanol (150 ml.) by neutralisation with sodium methoxide was added to o-nitrocinnamonitrile (6.96 g.) (S. Malinowski, Roczniki Chem., 1952, 26, 85) and the mixture was refluxed for 2 hr., then evaporated to ca. 15 ml. under reduced pressure. Ethyl acetate (150 ml.) was added, and the solution was extracted with 2N-hydrochloric acid (2 × 150 ml.). The acid extracts were neutralised with solid sodium hydrogen carbonate, giving a solid (3.3 g., 40%). Recrystallisation from aqueous methanol gave o-nitrocinnamamidoxime, m.p. 173°, λmax. 236, 265 nm, (ε 17150, 14700) (Found: C, 52.4; H, 4.5; N, 20.05. C9H9N3O3 requires C, 52.2; H, 4.4; N, 20.3%).
Reaction SMILES: [N:1]1([C:6]2[S:14][C:13]3[C:12]([C:15]#[N:16])=[CH:11][N:10]=[C:9]([NH:17]CC4C=CC(OC)=CC=4)[C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH:27]S(O)(=O)=O>>[NH2:17][C:9]1[C:8]2[CH:7]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[S:14][C:13]=2[C:12]([C:15]([NH2:16])=[O:27])=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc(-n4ccnc4)cc23)cc1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cnc(N)c2cc(-n3ccnc3)sc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-imidazol-1-yl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 37 (0.050 g, 0.14 mmol) was added H2SO4 (0.25 mL). After stirring at room temperature for 1 h, 2 g of ice were added to the solution. The precipitate was filtered, washed with H2O, then dissolved in 30% methanol, 2.5% triethylamine in CH2Cl2. The solution was concentrated, the solid was suspended in H2O, then filtered and rinsed with H2O resulting in pure 38. 1H NMR (400 MHz, d6-DMSO) δ 8.57 (s, 1H), 8.17 (s, 1H), 8.02 (bs, 1H), 7.77 (s, 1H), 7.67 (bs, 1H), 7.39 (bs, 1H), 7.18 (m, 3H).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.O1CCOCC1>O>[N+:17]([C:16]1[CH:15]=[CH:14][C:13]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[N:12][CH:11]=1)([O-:19])=[O:18]
Reactant: C1CN2CCC(CC2)N1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(N2CCN3CCC2CC3)nc1

Procedure:
1,4-diazabicyclo[3.2.2]nonane (6.3 g, 50 mmol) was added to a mixture of 2-chloro-nitropyridine (11.9, 75 mmol), and dioxane (250 ml) at 0° C. The reaction mixture was allowed to reach room-temperature. Water (100 ml) was added. The mixture was extracted with dichloromethane (3×50 ml). Chromatography on silica gel with dichloromethane and 10% methanol as solvent gave the title compound as an oil. Yield 8.1 g (65%). Mp. 143-146° C.
Reaction SMILES: B(O)(O)O.C1N2CN3CN(C2)CN1C3.[CH3:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1O)([CH3:18])[CH3:17].OS(O)(=O)=O.CC(C1C=C(C=C)C=C(C(C)(C)C)[C:40]=1[OH:51])(C)C>C(O)CO>[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:20]=1)[CH:40]=[O:51])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: OCCO
Product: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Temperature: 149 °C
Reaction time: 0.5 h

Procedure:
3.5 g of boric acid was heated in 150 ml of ethylene glycol at 150° C. for 30 minutes, in a 500 cc flask equipped with a reflux condenser. 25 g of hexamethylenetetramine and 21 g of 2,6-bis (1,1-dimethylethyl)phenol were then added and the solution maintained at 148-150° C. for 15 minutes. After cooling to 125° C. at which stage the first crystals appeared, 150 ml of H2SO4 (30% 0 was added and stirring was continued for another 30 minutes. The resulting slurry was filtered and washed with warm water. After drying, 22 g of 3,5-bis (1,1-dimethylethyl)benzaldehyde was obtained.