Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[C:5]([C:8]1[C:16]2[S:15][C:14]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:13][C:12]=2[CH:11]=[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=1)(=O)[CH3:6]>CN(C=O)C>[CH2:24]([O:23][C:10]1[CH:9]=[C:8](/[C:5](/[CH3:6])=[N:4]/[O:3][CH3:2])[C:16]2[S:15][C:14]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:13][C:12]=2[CH:11]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(C(C)=O)c2s1
Reactant: CON
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(/C(C)=N/OC)c2s1
Temperature: 60 °C
Yield: 78 %

Procedure:
O-Methyl hydroxylamine hydrochloride (289 mg, 3.46 mmol) was added to 1-(7-acetyl-5-benzyloxy-1,3-benzothiazol-2-yl)-3-ethyl-urea (650 mg, 1.73 mmol) in DMF (7 mL). The reaction mixture was heated to 60° C. for 2 h after which time LCMS indicated clean conversion to the desired product. The reaction was diluted with EtOAc, washed with water then brine and the organic layer dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound an off white solid, 550 mg, 78% yield.
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH2:20][C:21]([NH2:23])=[S:22]>C(Cl)Cl>[NH2:23][C:21]1[S:22][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:20]=1
Reactant: NC(N)=S
Reactant: CCCCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CCCCCc1nc(N)sc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
An equimolar mixture (18 mmol) of 2-chloro-1-(4-nitrophenyl)octan-3-one and thiourea is heated at 60° C. for 6 hours. The reaction mixture is taken up in methylene chloride and filtered. After concentration, the filtrate is washed with water which has been rendered basic, and extracted with chloroform to give 3 g of 2-amino-5-(4-nitrobenzyl)-4-pentylthiazole in the form of a brown oil, which is used as such for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:16]1([N:19]2[C:28]3[C:23](=[CH:24][C:25]([F:31])=[C:26](F)[C:27]=3[F:29])[C:22](=[O:32])[C:21]([C:33]([OH:35])=[O:34])=[CH:20]2)[CH2:18][CH2:17]1>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:15][CH2:14][CH:13]1[CH2:12][N:11]([C:26]1[C:27]([F:29])=[C:28]3[C:23]([C:22](=[O:32])[C:21]([C:33]([OH:35])=[O:34])=[CH:20][N:19]3[CH:16]3[CH2:18][CH2:17]3)=[CH:24][C:25]=1[F:31])[CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC12CCC1CNC2
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC12CCC1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 71 %

Procedure:
1.9 g of 1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]heptane and 0.83 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid were added to 15 ml of pyridine, followed by heating under reflux for 4 hours. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (using a 100:1 mixture of chloroform and methanol as the eluent) and recrystallization (from ethyl acetate-diisopropyl ether) to obtain 0.99 g of 7-[1-(t-butoxycarbonylamino)-3-azabicyclo[3.2.0]hept-3-yl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (m.p. 211-215° C.).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([Cl:25])[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]2[CH3:36])[C:20]=1[CH3:37]>CN(C)C=O>[ClH:25].[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[N:22]=[C:21]([N:26]2[CH2:35][CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]2[CH3:36])[C:20]=1[CH3:37]
Reactant: COCc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 46.6 %

Procedure:
After 4-fluoroaniline(0.43 ml, 4.5 mmol) and triethylamine(0.63 ml, 4.5 mmol) were added to a solution of 6-methoxymethyl-5-methyl-2-chloro-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.96 g, 3 mmol) in dimethylformamide(5 ml), 600 mg of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.C(Cl)[Cl:35]>>[ClH:35].[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1
Reactant: ClCCl
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Product: Cl
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of tert-butyl 4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 1, step e) (2.3 g) in DCM (50 mL) at 0° C. and the resulting mixture was stirred for 16 h. The solvent was evaporated in vacuo. Toluene (50 mL) was added and the mixture evaporated in vacuo. The residue was dissolved in methanol (20 mL) and applied to a SCX cartridge pre-wetted with methanol. The cartridge was washed with methanol (250 mL) and eluted with 3M ammonia in methanol solution (150 mL). The eluent was evaporated in vacuo and the residue, dissolved in MeCN (100 mL). HCl (1M solution in diethyl ether, 10 mL) was added and the solvent was evaporated in vacuo to give the subtitled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13]C([C@@H]3CCCN3C(=O)[C@H](NC(=O)C)CC3C=CC(C4C=CC=CC=4)=CC=3)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:41]([O:43][C:44]([NH:46][C@H:47]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1)[C:48]([N:50]1[CH2:54][CH2:53][CH2:52][C@H:51]1[C:55]([OH:57])=O)=[O:49])=[O:45])[CH3:42]>>[CH2:41]([O:43][C:44](=[O:45])[NH:46][C@H:47]([CH2:58][C:59]1[CH:60]=[CH:61][C:62]([O:65][CH3:66])=[CH:63][CH:64]=1)[C:48]([N:50]1[CH2:54][CH2:53][CH2:52][C@H:51]1[C:55](=[O:57])[NH:13][CH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH2:1])=[N:3][CH:4]=[CH:5]2)=[O:49])[CH3:42]
Reactant: CCOC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Product: CCOC(=O)N[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Yield: 79 %

Procedure:
Using the procedure described in example 97f 0.115 g of 1-(2-(R)-ethoxycarbonylamino-3-(4-methoxyphenyl)-propionyl)-pyrrolidin-2-(S)-carboxylic acid was converted into 0.130 g (79%) of the title compound. (+)-APCI-MS: 520 (MH+).
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].CN(C)CCN(C)C.[CH3:20][O:21][C:22]1[C:23]([O:32][CH2:33][O:34][CH3:35])=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=[O:26]>O1CCCC1>[CH3:23][O:32][CH2:33][O:34][C:8]1[CH:7]=[CH:6][CH:11]=[CH:10][C:9]=1[CH:25]([C:24]1[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:22]([O:21][CH3:20])[C:23]=1[O:32][CH2:33][O:34][CH3:35])[OH:26]
Reactant: CCCCCC
Reactant: COCOc1c(C=O)ccc(OC)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1ccccc1C(O)c1ccc(OC)c(OC)c1OCOC
Temperature: 0 °C
Yield: 200.1 %

Procedure:
A 1.6M solution of butyl lithium in hexane (91 ml, 146 mmol) was placed in an oven-dried 500 ml 3-necked flask and cooled to 0° C. and then 22.5 ml (20.1 mmol) of tetramethylethylenediamine was added with stirring. After a 10 min reaction period, a solution of 18.3 g (133 mmol) of methoxymethoxybenzine was added and the mixture allowed to stir for about 3.5 hours at 0° C. 3,4-Dimethoxy-2-methoxymethoxybenzaldehyde (30.0 g, 133 mmol) in 18 ml of tetrahydrofuran was then added dropwise with stirring. The mixture was allowed to warm to room temperature and stir for 1 hour and was then quenched with 50 ml of saturated aqueous ammonium chloride. The resulting mixture was extracted with 200 ml of ethyl acetate three times. The combined extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain 48.5 g of an oil. This was purified by silica gel chromatography on an 8 in. diameter sintered glass funnel eluting with mixtures of hexane and dichloromethane increasing from 38 percent to 75 percent dichloromethane to obtain 32.2 g (68 percent of theory) of the title compound as a yellow oil. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.C(O[C:15](=O)[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](=[O:28])N(OC)C)[CH2:19][CH2:18]1)(C)(C)C.[O:30]=[C:31]1[NH:36][C:35]2[CH:37]=[C:38](C=O)[CH:39]=[CH:40][C:34]=2[O:33][CH2:32]1>>[S:9]1[C:8]([C:23]([C@H:20]2[CH2:19][CH2:18][C@H:17]([NH:16][CH2:15][C:38]3[CH:39]=[CH:40][C:34]4[O:33][CH2:32][C:31](=[O:30])[NH:36][C:35]=4[CH:37]=3)[CH2:22][CH2:21]2)=[O:28])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: c1ccc2sccc2c1
Product: O=C1COc2ccc(CN[C@H]3CC[C@H](C(=O)c4cc5ccccc5s4)CC3)cc2N1

Procedure:
The title compound was prepared according to the same protocol as that described for example 1, steps 1.a to 1.c, starting from thianaphthene (5 mmol), [trans-4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.5 mmol) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.4 mmol). A colourless solid (44 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.Cl.Cl.Cl.[N:17]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:17]1([CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([NH:32][C:11]([C:5]3[NH:6][C:7]4[C:3]([CH:4]=3)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)=[O:13])[CH2:30][CH2:31]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
4-Bromo-1H-indole-2-carboxylic acid (1.5 g, 3.1 mmol), 1-(2-azepan-1-yl-ethyl)-piperidin-4-ylamine tri-hydrochloride (5) (2.1 g, 3.1 mmol) and DIEA (4.3 ml, 12.4 mmol) are dissolved under argon atmosphere in DMF (25 ml). TBTU (2.3 g, 3.4 mmol) is added at room temperature. The reaction mixture is stirred for 2 h at r.t., evaporated under high vacuum, dissolved in ethyl acetate and washed twice with 5% aqueous NaHCO3 solution. The organic layers are dried over sodium sulfate. Evaporation under reduced pressure gave 1.3 g (93%) of a beige solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[C-:18]#[N:19].[K+]>CS(C)=O.O>[Cl:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)=[N:7][C:2]([C:18]#[N:19])=[N:3][CH:4]=1
Reactant: Clc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
A mixture of 2-bromo-5-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (3.0 g, 9.54 mmol, 1.0 eq), KCN (1.24 g, 19.07 mmol, 2.0 eq) and 1,4-diazobicyclo[2,2,2]octan (DABCO.6H2O) (4.20 g, 19.07 mmol, 2.0 eq) in DMSO (50 mL) and H2O (10 mL) was stirred at 80° C. for 4 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (CH2Cl2/MeOH 500:1 to 50:1 as eluent) to afford 5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidine-2-carbonitrile (1.9 g, 77%) as a solid. LC-MS (m/z)=261.0 [M+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[F:10][C:11]1[C:18]([F:19])=[C:17]([C:20](F)(F)F)[C:16]([F:24])=[C:15]([F:25])[C:12]=1[CH2:13]Br.C[N:27](C=O)C>>[Cl:9][C:4]1[CH:3]=[CH:2][C:7]([NH:27][CH2:13][C:12]2[C:11]([F:10])=[C:18]([F:19])[C:17]([CH3:20])=[C:16]([F:24])[C:15]=2[F:25])=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: CN(C)C=O
Product: Cc1c(F)c(F)c(CNc2ccc(Cl)c(O)c2)c(F)c1F
Yield: 76 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 4-amino-2-chlorophenol (3.00 g, 19.6 mmole), DMF (80 ml), TEA (0.5 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.40 g, 8.36 mmole), 2.00 g (76.0% yield) of 2-chloro-5-(2,3,5,6-tetrafluoro-4-methylbenzylamino)phenol was obtained as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][CH:10]=1)=[O:8].[OH-].[Na+:21]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O-:19])=[O:18])[C:12]2=[CH:11][CH:10]=1)=[O:8].[Na+:21]
Reactant: Cn1cccc1C(=O)c1ccc2n1CCC2C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cccc1C(=O)c1ccc2n1CCC2C(=O)[O-]

Procedure:
To a solution of 300 mg. of 5-(N-methyl-2-pyrroyl)-1,2 -dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of methanol is added 1 molar equivalent of sodium hydroxide, in the form of a 0.1N solution. The solvent is then evaporated under reduced pressure and the residue taken up in 2 ml. of methanol, followed by precipitation with ether, to yield crude sodium 5-(N-methyl -2-pyrroyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]pyrrole-1-carboxylate which can be crystallized from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:45])[C@H:11]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:33][CH:32]=2)[NH:12][C:13](=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21]C(OC(C)(C)C)=O)=[CH:16][CH:15]=2)[CH2:3]1.[ClH:46].O1CCOCC1>>[ClH:46].[CH3:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([NH:9][C:10](=[O:45])[C@H:11]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:35][CH:36]=2)[NH:12][C:13](=[O:29])[C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=2)[CH2:3]1
Reactant: CC1CCC(NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1C
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCC(NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)c2ccc(CN)cc2)CC1C

Procedure:
N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine (0.3 g) and 3,4-dimethylcyclohexylamine (0.1 g) were dissolved in dry methylene chloride (30 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.2 g) was added to the solution, followed by stirring at room temperature for 12 hours. According to a conventional post-treatment, N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide (I) (0.32 g) was obtained. The above compound (I) (0.3 g) was allowed to react with 4N-hydrogen chloride/dioxane solution to obtain 4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide hydrochloride (II) (0.26 g). The above compound (II) (0.26 g) and 4-(t-butyloxycarbonyl)aminomethylbenzoic acid (0.16 g) were dissolved in dry methylene chloride (20 ml)-pyridine solution, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g) was added to the solution. The reaction was carried out at room temperature for 12 hours. After a conventional post-treatment, N-[4-(t-butyloxycarbonyl)aminomethylbenzoyl]-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide (III) (0.23 g) was obtained. The above compound (III) was allowed to react with 4N-hydrogen chloride/dioxane solution to (2 ml) obtain N-(4-aminomethylbenzoyl)-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide hydrochloride (0.18 g).
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[C:13]=1[Cl:21])(=[O:4])=[O:3].[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[Br:29]>>[Br:29][C:24]1[C:25]([CH3:28])=[N:26][O:27][C:23]=1[NH:22][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[C:13]=1[Cl:21])(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccsc1COc1ccc2c(c1Cl)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccsc2COc2ccc3c(c2Cl)OCO3)c1Br
Yield: 47 %

Procedure:
N-(4-bromo-3-methyl -5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene with 5-amino-4-bromo-3-methylisoxazole, 47% yield, m.p. 152-154° C.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[CH3:21][O:22][C:23]([O:31][Si](C)(C)C)=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[NH:17]1[C:18]2[C:14](=[CH:13][C:12]([CH:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:23]([O:22][CH3:21])=[O:31])=[CH:20][CH:19]=2)[CH:15]=[N:16]1
Reactant: CC(=O)OC(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: COC(=Cc1ccccc1)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a solution of (1H-indazol-5-yl)(phenyl)methyl acetate (245 mg, 0.8 mmol) and (1-methoxy-2-phenylvinyloxy)trimethylsilane (1.78 g, 8.0 mmol, prepared using General Silyl Ketene Acetal Method A) in 20 mL of dry DCM was added TiCl4 (0.8 mL of 1.0 M DCM solution, 0.8 mmol) and then stirred 3 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. MPLC purification using a 0-40% EtOAc/hexane gradient gave 170 mg (60% yield) of methyl 3-(1H-indazol-5-yl)-2,3-diphenylpropanoate. MS found: (M+H)+=357.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[Cl:11][C:12]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:13]=1[CH2:14][C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1>>[N:2]1([CH2:7][C:8]([N:18]2[CH2:19][C@H:15]([CH2:14][C:13]3[CH:37]=[CH:38][C:39]([Cl:41])=[CH:40][C:12]=3[Cl:11])[CH2:16][C@H:17]2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2Cl)CN1
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2Cl)CN1C(=O)Cn1cncn1
Yield: 35 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(2,4-dichlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 180, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(2,4-dichlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (48 mg, 35%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.03 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.68-7.35 (m, 5H), 7.19 (t, 2H), 7.07-6.88 (m, 4H), 5.24 (q, 2H), 4.57-4.48 (m, 1H), 3.91-3.78 (m, 1H), 2.97-2.70 (m, 3H), 2.11-1.88 (m, 3H). MS (EI) for C28H24FN5O3. found 569.8 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7]2[C:15]3[N:11]([C:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)=[C:13]4[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:14]4=3)[CH2:10][CH:9]([CH2:31][OH:32])[CH:8]=2)[S:5][CH:6]=1>[Pt].C(O)C.O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]2[C:15]3[N:11]([C:12]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)=[C:13]4[C:19](=[O:20])[N:18]([CH3:21])[C:17](=[O:22])[N:16]([CH3:23])[C:14]4=3)[CH2:10][CH:9]([CH2:31][OH:32])[CH2:8]2)[S:5][CH:6]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)=CC(CO)C3
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CC(CO)C3
Reaction time: 72 h

Procedure:
A mixture of 10-(4-Chlorothiazol-2-yl)-5-(3-fluorophenyl)-8-(hydroxymethyl)-1,3-dimethyl-7,8-dihydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione (310 mg, 0.66 mmol) and 10% platinum on carbon (310 mg) in ethanol (22 mL) and tetrahydrofuran (22 mL) was stirred under an atmosphere of hydrogen for 3 days. The reaction mixture was filtered and the filtrates concentrated under vacuum. The residue was dissolved in ethanol (22 mL) and tetrahydrofuran (22 mL), fresh 10% platinum on carbon (310 mg) was added and the mixture further stirred under an atmosphere of hydrogen for 5 days. The reaction mixture was filtered and the filtrates evaporated under vacuum. The residue was dissolved in 10 mL of 5% MeOH/DCM and the solution was treated with silica-TMT (trimercaptotriazine functionalized silica, ˜1 g) for 5 minutes, then filtered. The residue was washed with 5% MeOH/DCM and the filtrates evaporated under vacuum.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH:13]=[O:14])[C:7]([OH:9])=[O:8].[CH3:15]I.Cl>CN(C=O)C>[CH3:15][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:12]([CH:13]=[O:14])=[C:4]([F:3])[CH:5]=1
Reactant: CI
Reactant: O=Cc1ccc(C(=O)O)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% NaH (0.14 mol) is added portionwise to a solution of 3-fluoro-4-formyl benzoic acid (3, 0.12 mol) in dry DMF (330 mL). The mixture is stirred at room temperature for 30 min. Methyl iodide (0.14 mol) is added dropwise to the mixture. After stirring at room temperature for 5 h, the reaction mixture is poured into 1 N HCl (ca. 1000 mL) and extracted twice with EtOAc. The combined organic layers are washed with saturated aqueous NaHCO3, brine, dried over MgSO4, and evaporated in vacuo to give crude 3-fluoro-4-formyl benzoic acid methyl ester (4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>C1COCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][N:3]=2)[CH:20]=1
Reactant: Nc1ccncn1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccncn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To 4-aminopyrimidine (1.0 g, 10.52 mmol) in THF (40 ml) at 0° C. under nitrogen was added potassium tert-butoxide (2.46 g, 22 mmol). After stirring for 5 min 2,4-difluoronitrobenzene (1.672 g, 10.52 mmol) was added dropwise. The reaction was stirred for 1 h at 0° C. then at 20° C. for 1 h, then quenched with 5% citric acid to give a pH of 5. The mixture was extracted with EtOAc (150 mL), dried (Na2SO4) and evaporated to an orange gum. This was purified by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM to give the title compound as a yellow solid, (0.31 g, 12%). LCMS (Method B): RT=2.16 min, [M+H]+=234.91