Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH2:22][C:23](OCC)=[O:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].CO>O1CCCC1>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([CH2:22][CH2:23][OH:24])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Reaction time: 0.33 h
Yield: 112.1 %

Procedure:
Ethyl [6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidin-4-yl]acetate (3.0 g) was dissolved in tetrahydrofuran (40 mL), and cooled in an ice bath. Sodium tetrahydroborate (884 mg, 23.4 mmol) was added followed by methanol (4.8 mL, 120 mmol), in portions. The reaction mixture was stirred for 20 min, removed the ice bath, and stirred at 21° C. for 0.5 hour. HPLC & LCMS showed no remaining ester, and showed conversion to the desired M+H 349; and also showed several over reduction products (at least one of which has no UV absorbance). The reaction mixture was quenched with water and evaporated. The reaction mixture was diluted with aqueous bicarbonate and EtOAc, and stirred for 0.5 hour. The EtOAc layer was washed with brine, dried (Na2SO4), and evaporated to give 3.0 g oil. The product was purified by chromatography on a 120 g silica gel column, using solvent A=hexane; solvent B=3% iPA/EtOAc; flow 60 mL/min; A, 3 min; Gradient to 50% B in 30 min, then 50% B for 15 min; detector set at 254 nm; collected 47 mL fractions; retention time, 34 min. evaporated to yield 1.5 g, a light yellow viscous oil, 56% yield. 1H NMR (300 MHz, DMSO-D6): δ7.10 (s, 1H); 5.20 (m, 1H, OCH); 4.71 (t, 1H, OH); 3.85 (s, 4H, OCH2); 3.72 (q, 2H, OCH2); 2.85 (t, 2H, CH2); 1.5-2.0 (m, 8H).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]([C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-].[K+]>CO>[C:3]([CH2:5][CH2:6][NH:7][C:8]1[CH:9]=[C:10]([C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCNc1cccc(-c2cc(Cc3cnc(N)nc3N)cc(OC)c2OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(Cc2cnc(N)nc2N)cc(-c2cccc(NCCC(=O)O)c2)c1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 29.1 %

Procedure:
640 mg of 5-(3'-(2-methoxycarbonylethyl-amino)-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine (Example 4n)) are treated with 8 ml of a 1M solution of potassium hydroxide in methanol and stirred at room temperature for 10 hrs. Insoluble material is filtered off from the mixture and the filtrate is concentrated. The residue is chromatographed on MCl-Gel CHP20P (Mitsubishi Corporation) with water/acetonitrile 3:1. 180 mg (26%) of 5-(3'-(2-carboxyethyl-amino)-5,6-dimethoxy-biphenyl-3-ylmethyl)-pyrimidine-2,4-diamine are isolated as a white yellowish solid. M.p. 136°-140° (decomposition).
Reaction SMILES: [CH3:1][CH:2]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[C:3]([O:5]CC)=O.[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH2:24]>>[CH3:14][C@H:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([CH3:21])[N:16]1[CH2:22][CH2:23][NH:24][C:3](=[O:5])[CH:2]([CH3:1])[N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13]
Reactant: CCOC(=O)C(C)N1CCCC1=O
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Product: CC(C(=O)NCCN1[C@H](C)CCC[C@@H]1C)N1CCCC1=O
Reaction time: 20 h

Procedure:
A mixture of 9.25 g. of ethyl α-methyl-2-oxo-1-pyrrolidineacetate (British Pat. No. 1,309,692) and 11.2 g. of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine is heated under nitrogen and an air condenser plugged with cotton for 20 hours at 150° C. The excess cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine is evaporated at reduced pressure and the residue is fractionated. The product, cis-(±)-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-α-methyl-2-oxo-1-pyrrolidineacetamide, is obtained as an oil, b.p. 168°-170° C./0.1 mm.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])([O-:8])=[O:7]>>[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:1]([CH:2]([CH3:4])[CH3:3])[OH:5])([O-:8])=[O:7]
Reactant: CC(C)C=O
Reactant: Cc1ccccc1[N+](=O)[O-]
Product: CC(C)C(O)Cc1ccccc1[N+](=O)[O-]
Yield: 2.2 %

Procedure:
JP-A-62-202091 describes the reaction of isobutyraldehyde with 2-nitrotoluene, which afforded only 2.2% 2-(2-nitrophenyl)-1-isopropylethanol.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].[BrH:14]>>[BrH:14].[BrH:14].[NH2:10][CH2:11][CH2:12][S:13][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCc1ccccn1
Reactant: NCCS
Agent: Br
Agent: Cl
Product: NCCSCc1ccccn1

Procedure:
(a) A solution of 2-hydroxymethyl pyridine (5.45 g.) and cysteamine hydrochloride (6.2 g.) in aqueous hydrobromic acid (110 ml., 48%) was heated under reflux overnight. After cooling, the solution was evaporated to dryness and the residual solid washed with ethanol/ether and recrystallised from aqueous ethanol to give 2-[(2-aminoethyl)thiomethyl]pyridine dihydrobromide m.p. 191°-193°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:21][C:15]2[N:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]=2[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[C:30]1([CH2:33][N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH2:32][O:31]1.C[O-].[Na+]>C(O)(C)(C)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:21][C:15]2[N:16]=[CH:17][N:18]([CH2:32][C:30]([C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[F:22])([OH:31])[CH2:33][N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)[C:19](=[O:20])[C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cnc2sc(CCCOCc3ccccc3)cc12
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=c1c2cc(CCCOCc3ccccc3)sc2ncn1CC(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 14 %

Procedure:
6-(3-Benzyloxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A02) (3.0 g, 0.01 mole), 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5) (2.82 g, 0.012 mole) and sodium methoxide (0.65 g, 0.012 mole), were taken in two neck round bottom flask under inert atmosphere, dry t-butanol (70 ml) was added to the above reaction mixture and the mixture was stirred under reflux for 12 hours. t-Butanol was removed on rotavapor, water (50 ml) was added to the reaction mixture, the compound from the reaction mixture was extracted with ethyl acetate (3×50 ml), dried, concentrated and purified by column chromatography to obtain the pure 6-(3-benzyloxypropyl)-3-[2-(2,4-difluorophenyl)-2-hydroxy-3-[1,2,4]triazol-1-ylpropyl]-thieno[2,3-d]pyrimidin-4(3H)-one (1-A02) (0.8 gm, 14%). 1HNMR (CDCl3, 200 MHz):: 1.91-2.06 (m, 2H), 2.95 (t, J=6 Hz, 2H), 3.51 (t, J=6 Hz, 2H), 4.21 (d, J=14 Hz, 1H), 4.49 (s, 2H), 4.52 (d, J=14 Hz, 1H), 4.72 (d, J=14 Hz, 1H), 4.79 (d, J=14 Hz, 1H), 6.22 (s, 1H), 6.72-6.88 (m, 2H), 7.08 (s, 1H), 7.31 (bs, 5H), 7.49-7.62 (m, 1H), 7.83 (s, 1H), 7.91 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Si](C)(C)C)=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:25]=1[CH:26]=[O:27].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:26]([C:25]2[C:28]([O:32][CH3:33])=[CH:29][CH:30]=[CH:31][C:24]=2[Cl:23])[OH:27])=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc(Cl)c1C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(Cl)c1C(O)Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A solution of (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester (1.00 g, 3.08 mmol) and 2-chloro-6-methoxybenzaldehyde (526 mg, 3.08 mmol) in THF (10 mL) was added tetra-butylammonium fluoride (121 mg, 462 μmol) at 25° C., the color of the solution changed to dark blue after the addition. The reaction mixture was stirred at 25° C. for 30 min and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded {4-[2-(2-chloro-6-methoxy-phenyl)-2-hydroxy-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (0.45 g, 35%) as an oil.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([OH:23])[C:10]2[CH:15]=[CH:14][N+:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CO.[BH4-].[Na+]>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH:11]=2)[OH:23])=[CH:5][CH:4]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(C1=CCN(Cc2ccccc2)CC1)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a stirred solution of 140.5 parts of 4-[bis(4-fluorophenyl)hydroxymethyl]-1-(phenylmethyl)pyridinium bromide in 640 parts of methanol were added portionwise, during a 2 hours-period, 15.1 parts of sodium borohydride at room temperature (cooling in ice-water was necessary). Upon completion, the whole was stirred and refluxed for 30 minutes. After cooling to room temperature, 800 parts of water were added. The whole was allowed to stand overnight. The reaction mixture was evaporated till all traces of methanol were removed. 1040 Parts of dichloromethane were added. The layers were separated. The organic layer was washed with 200 parts of water, dried, filtered and evaporated. The residue was taken up in dry methylbenzene and the whole was evaporated, yielding 111 parts (94.5%) of α,α-bis(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol as an oily residue (intermediate 28).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1.CN(C=O)C.C1C=CC=CC=1>O>[O:21]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:16]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccco1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc(N=Cc2ccco2)cc1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2 g), furfural (1.41 g), DMF (25 ml) and benzene (25 ml) was refluxed in an apparatus equipped with a Dean-Stark water separator for 3 hours. The reaction mixture was evaporated in vacuo and the resultant residue was triturated with diethyl ether to give 6-[4-(2-furylmethylenamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.47 g).
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][C@H:46]2[CH2:51][CH2:50][C@H:49]([C@H:52]3[CH2:57][CH2:56][C@H:55]([CH:58]=O)[CH2:54][CH2:53]3)[CH2:48][CH2:47]2)=[CH:40][CH:39]=1)#[N:37]>C(OCC)(=O)C>[F:2][CH2:3][CH2:4][CH:5]=[CH:58][C@H:55]1[CH2:56][CH2:57][C@H:52]([C@H:49]2[CH2:50][CH2:51][C@H:46]([CH2:45][CH2:44][C:41]3[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[CH:39][CH:40]=3)[CH2:47][CH2:48]2)[CH2:53][CH2:54]1
Reactant: N#Cc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](C=CCCF)CC3)CC2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (15.1 g, 37.4 millimols) with THF (70 ml) was cooled down to -20° C., followed by adding t-BuOK (4.2 g, 37.4 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (100 ml) solution of trans-4-(trans-4-(2-(4-cyanophenyl)ethyl)cyclohexyl)cyclohexanecarbaldehyde (11.0 g, 34.0 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2, except that the quantity of ethyl acetate was made 500 ml, to obtain raw 4-(2-(trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)ethyl)benzonitrile (11.3 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([N:23]([CH3:32])[C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C(O)=O>CSC.C(S)(S)C>[NH2:1][C@@H:2]([C:13]([NH:15][C@H:16]([C:21]([N:23]([CH3:32])[C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:19])[CH3:20])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Agent: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Yield: 37 %

Procedure:
Condensation of BocDTrp-LeuOH (Example 38, 2.09 g.) and MeNleNH2 (1.00 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocDTrp-Leu-MeNleNH2 in 99% yield. De-t-butoxycarbonylation of BocDTrp-Leu-MeNleNH2 (2.50 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-Leu-MeNleNH2 in 37% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][C:18]#[N:19])[N:7]=1)[CH3:2].Cl.N[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[C:24]=1[SH:31]>C(O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][C:18]2[S:31][C:24]3[C:25]([F:30])=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[N:19]=2)[N:7]=1)[CH3:2]
Reactant: Nc1cc(F)cc(F)c1S
Reactant: CCOC(=O)Cc1nn(CC#N)c(=O)c2ccccc12
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nn(Cc2nc3cc(F)cc(F)c3s2)c(=O)c2ccccc12

Procedure:
A mixture of ethyl-3-cyanomethyl-4-oxo-phthalazin-1-ylacetate (1.29 g), 2-amino-4,6-difluoro-thiophenol hydrochloride (0.98 g) and ethanol (20 ml) was refluxed for 6 hours. Upon cooling, the title compound precipitated out as a pale yellow solid (yield: 1.62 g; m.p. 115°-117° C.).
Reaction SMILES: [CH2:1]([C@H:3]1[C:8](=O)[N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][C:5](=O)[NH:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([C@H:3]1[CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][NH:4]1)[CH3:2]
Reactant: CC[C@@H]1NC(=O)CN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H]1CN(Cc2ccccc2)CCN1
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 8.1 gm (34.9 mmol) 2(S)-ethyl-4-benzyl-3,6-dioxopiperazine in 50 mL tetrahydrofuran was added dropwise via addition funnel to a solution of 75 mL (75 mMol) lithium aluminum hydride (1M in tetrahydrofuran) and the mixture was heated at reflux for 2.5 h. The reaction was then cooled in an ice bath and was treated sequentially with 3 mL deionized water, 3 mL 5N sodium hydroxide, and 9 mL deionized water. The resulting slurry was allowed to stir for 1 hour and was then filtered. The recovered salts were rinsed with 100 mL tetrahydrofuran and 100 mL dichloromethane. The filtrate was concentrated in vacuo to afford 7.03 g (99%) of the desired piperazine.
Reaction SMILES: [BrH:1].[F:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH:5]([C:13]1(O)[N:17]2[CH2:18][CH2:19][CH2:20][N:21]=[C:16]2[S:15][CH2:14]1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1>CC(C)=O>[BrH:1].[F:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH:5]([C:13]1[N:17]2[CH2:18][CH2:19][CH2:20][N:21]=[C:16]2[S:15][CH:14]=1)[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1
Reactant: OC1(C(c2ccc(F)cc2)c2ccccc2F)CSC2=NCCCN21
Agent: Br
Solvent: CC(C)=O
Product: Fc1ccc(C(C2=CSC3=NCCCN23)c2ccccc2F)cc1

Procedure:
A test tube containing 1.0 g. of 3-[o-fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidine-3-ol hydrobromide is immersed in an oil bath at 215° C. for 20 minutes. The compound decomposes, becomes liquid and then rehardens. A 5 ml. portion of acetone is added and the mixture is stirred and filtered. The crystalline product is washed with acetone and dried in vacuo, giving the desired product, m.p. 291°-293° C.
Reaction SMILES: [Cl:1][C:2]1[O:25][C:5]2=[C:6]([N:10](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:26].Cl.O1CCOCC1>>[Cl:1][C:2]1[O:25][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:26]
Reactant: Cc1c(Cl)oc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(Cl)oc2c(N)nccc12
Temperature: 55 °C
Yield: 65.3 %

Procedure:
Di-tert-butyl (2-chloro-3-methylfuro[2,3-c]pyridin-7-yl)imidodicarbonate (3.2 g, 8.38 mmol) DCM (25 mL) was cooled in an ice bath and treated with 4 N HCl in 1,4-dioxane (12.5 mL, 50 mmol) added slowly over several minutes. The reaction was removed from the cooling bath and heated at 55° C. for 16 h. The mixture was concentrated in vacuo and the residue was suspended in DCM and treated with saturated NaHCO3 until the pH reached ˜8.5. The organic layer was washed with water, then brine and then dried over anhydrous Na2SO4. After concentration in vacuo, the material was purified by flash chromatography (3% MeOH:DCM) to provide 1.0 g (66%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J=5.4 Hz, 1H), 6.79 (d, J=5.4 Hz, 1H), 4.78 (br s, 2H), 2.16 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:35])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC4C=CC=CC=4)[CH:22]=3)=[O:17])=[CH:11][C:10]=2[F:36])[CH:5]=[CH:4][N:3]=1>CCOC(C)=O.CO.[Pd]>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19](=[O:35])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[O:17])=[CH:11][C:10]=2[F:36])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3cccc(OCc4ccccc4)c3)cc2F)ccn1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ccc(NC(=O)NC(=O)Cc3cccc(O)c3)cc2F)ccn1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-3-(2-(3-(benzyloxy)phenyl)acetyl)urea (150 mg, 0.31 mmol) in a mixture of 5 mL of EtOAc and 3 mL of MeOH was added 10% Pd/C (200 mg). The suspension was stirred under H2 atmosphere for 1 h. Filtration, followed by concentration, provided the title compound (77 mg, 63%). 1H NMR (DMSO-d6) δ 10.95 (s, 1H), 10.54 (s, 1H), 9.35 (s, 1H), 7.74 (d, 1H, J=6.0 Hz), 7.68 (dd, 1H, J=13.0, 2.0 Hz), 7.30 (dd, 1H, J=9.0, 1.1 Hz), 7.23 (t, 1H, J=9.0 Hz), 7.07 (t, 1H, J=8.0 Hz), 6.69 (s, 1H), 6.68 (d, 1H, J=7.0 Hz), 6.62 (dd, 1H, J=7.0, 2.0 Hz), 6.10 (dd, 1H, J=6.0, 2.0 Hz), 5.90 (s, 2H), 5.73 (d, 1H, J=2.0 Hz), 3.27 (s, 2H); MS (ESI+) m/z 397 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.IC.[C:15](=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc2[nH]ccc2c1
Agent: [Cs+]
Solvent: CI
Product: CC(=O)c1ccc2c(ccn2C)c1
Yield: 51.5 %

Procedure:
Ex-28A: To a solution of 1-(1H-indol-5-yl)-ethanone (Yang, Y. et al, Heterocycles, 1992, 34(6), 1169–1175; 0.45 g, 2.8 mmol) were added iodomethane (3 mL) and cesium carbonate (2.3 g, 7.1 mmol). The reaction mixture was allowed to stir at 55° C. for 1.5 day during which additional iodomethane (11 mL) was added. The reaction was quenched with water. The aqueous solution was extracted with ether. The solution of ether was washed with saturated solution sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography. Elution with ethyl acetate (33%, v/v, in hexane) gave 1-(1-methyl-1H-indol-5-yl)-ethanone (0.25 g, 51%). 1H NMR (CDCl3) δ 8.30 (s, 1H), 7.91 (dd, J=1.2, 8.1 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.12 (d, J=3.2 Hz, 1H), 6.61 (d, J=3.0, 1H), 3.82 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: Cl.OS(O)(=O)=O.C[O:8][CH:9](OC)[CH2:10][N:11]1[C:15]([C:16]2[S:25][C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:24])[C:18]=3[CH:17]=2)=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:13]=[CH:12]1.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:24][C:23]1[C:18]2[CH:17]=[C:16]([C:15]3[N:11]([CH2:10][CH:9]=[O:8])[CH:12]=[N:13][C:14]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[S:25][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: COC(Cn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1)OC
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC=O)cc12
Temperature: 60 °C
Yield: 73.9 %

Procedure:
2M HCl (8 mL) and conc. H2SO4 (0.5 mL) were added to a solution of 6-[1-(2,2-dimethoxyethyl)-4-phenyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Example 64) (1.54 g) in THF (20 mL). The reaction was heated at 60° C. for 72 hours, allowed to cool to ambient temperature and then poured into NaHCO3 (aq. 50% sat.) (100 mL). The resultant precipitate was filtered to afford the title compound as a pale yellow solid (1 g, 74%) (used without further purification);
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([C:41]4[CH:45]=[CH:44][O:43][N:42]=4)[CH2:25][C:26](N4[C@@H](CC5C=CC=CC=5)COC4=O)=[O:27])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH:46]O.[Li+].[OH-].Cl>C1COCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C@@H:24]([C:41]4[CH:45]=[CH:44][O:43][N:42]=4)[CH2:25][C:26]([OH:27])=[O:46])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ccc(COc3ccc([C@H](CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c4ccon4)cc3)s2)cc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc(COc3ccc([C@H](CC(=O)O)c4ccon4)cc3)s2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
To a solution of 60.6 (26 mg, 0.042 mmol) in THF (0.4 mL) were added 30% H2O2 (47 μL, 0.42 mmol) and 1N LiOH (0.21 mL, 0.21 mmol) at 0° C. The mixture was stirred for 1 h at 0° C., adjusted to pH 3 with aqueous HCl, and extracted with EtOAc. The combined organics were washed with 1N Na2SO3 (pH 3) and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (10-45% EtOAc/hexane) and further purified by preparative thin layer chromatography (50% EtOAc/hexane) to afford 60 (1.6 mg, 8%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, 1H), 7.48 (d, 2H), 7.18 (m, 4H), 7.14 (d, 1H), 7.04 (d, 1H), 6.94 (d, 2H), 6.07 (d, 1H), 5.17 (s, 2H), 4.55 (t, 1H), 3.35 (dd, 1H), 2.98 (dd, 1H), 2.61 (t, 2H), 1.60 (m, 2H), 1.37 (m, 2H), 0.93 (t, 2H).