Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]([NH:5][C:6]1[S:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=1)=[O:4])[NH2:2].[CH:17](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:11][C:9]1[N:10]=[C:6]([N:5]2[C:3](=[O:4])[NH:1][N:2]=[CH:17]2)[S:7][C:8]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COC(OC)OC
Reactant: CCOC(=O)c1sc(NC(=O)NN)nc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Yield: 73 %

Procedure:
A solution of ethyl 2-(hydrazinecarboxamido)-4-methylthiazole-5-carboxylate (0.50 g, 2.05 mmol), trimethyl orthoformate (0.25 mL, 2.28 mmol) and p-toluenesulfonic acid monohydrate (10 mg) in methanol (10 mL) was subjected to microwave irradiation for 10 minutes at 90° C. (30 psi). The solvent was removed in vacuo and the residue was suspended in dichloromethane. The solid was collected by filtration, washed with saturated sodium bicarbonate and water, and dried to afford the title compound in 73% yield (0.38 g): 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 4.32 (q, J=6.9 Hz, 2H), 2.68 (s, 3H), 1.35 (t, J=6.9 Hz, 3H); MS (ES+) m/z 255.2 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:20][NH:21][C:22](=O)[O:23]C1C=CC=CC=1>CN(C)C=O>[CH3:20][NH:21][C:22]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:23]
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: CNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
Sodium hydride (430 mg, 10.75 mmol) was suspended in N,N-dimethylformamide (25 ml) under nitrogen atmosphere, and 4-(1H-5-indolyloxy)-2-pyridinamine (2.253 g, 10.00 mmol, CAS No. 417722-11-3) described in WO 02/32872 was gradually added while stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice water bath, and then phenyl N-methylcarbamate (1.587 g, 10.50 mmol) was added. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous sodium sulfate. The solvent was removed by distilled off. The crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (2.163 g, 7.66 mmol, 76.6%) as pale brown crystals.
Reaction SMILES: C(CC(O)=O)C.[C:7]([N:14](C(OC(C)(C)C)=O)[C@H:15]([C:22]([OH:24])=O)[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C[N:33]1CCOCC1.ClC(OCC(C)C)=O.N[C@@H](CC(C)C)CSCC>C(OCC)(=O)C>[C:7]([NH:14][C@H:15]([C:22]([NH2:33])=[O:24])[CH2:16][C:17]1[N:21]=[CH:20][NH:19][CH:18]=1)([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CCSC[C@@H](N)CC(C)C
Solvent: CCOC(C)=O
Solvent: CCCC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(N)=O
Reaction time: 0.25 h

Procedure:
A mixture of NαNim -bis BOC-(S)-histidine ethyl acetate solvate (0.96 g, 2.50 mmol), 4 methyl-morpholine (0.28 mL, 2.50 mmol) and isobutyl chloroformate (0.33 mL, 2.50 mmol) in ethyl acetate (35 mL) is stirred in an ice bath under N2 for 15 minutes. A solution of (S)-2-amino-1-ethylthio-4-methyl pentane (0.40 g, 2.50 mmol) in ethyl acetate (2 mL) is then added and the reaction stirred at room temperature for 18 hours. After washing with 10% citric acid, brine, saturated NaHCO3 solution and brine, the ethyl acetate extract is dried (Na2SO4), filtered and concentrated under reduced pressure. The residue is flash chromatographed over silica gel. Elution with a mixture of 2% methanol- 98% chloroform affords pure BOC-protected histidineamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.O=[CH:34][C@@H:35]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[C:40]([O:39][C:38]([NH:37][C@@H:35]([CH3:36])[CH2:34][NH:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1)=[O:44])([CH3:43])([CH3:42])[CH3:41]
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](CNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), (S)-tert-butyl 1-oxopropan-2-ylcarbamate (86 mg) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed and the product was carried on to next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1.[Br:30][C:31]1[N:36]=[C:35]([C:37](O)=[O:38])[C:34]([NH2:40])=[CH:33][CH:32]=1>>[NH2:40][C:34]1[C:35]([C:37]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][C@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@H:10]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]2)=[O:38])=[N:36][C:31]([Br:30])=[CH:32][CH:33]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(c2ccncc2N)C1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(c2ccncc2NC(=O)c2nc(Br)ccc2N)C1

Procedure:
Following Method 11 of Example 305, tert-butyl (3S,5R)-1-(3-aminopyridin-4-yl)-5-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and 6-bromo-3-aminopicolinic acid were coupled to yield tert-butyl (3S,5R)-1-(3-(3-amino-6-bromopicolinamido)pyridin-4-yl)-5-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate. LCMS (m/z): 621.1/623.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[C:12]([CH3:13])=[C:11]([OH:14])[CH:10]=[C:9]([CH3:15])[C:8]=1[F:16])=O>C1COCC1>[F:16][C:8]1[C:9]([CH3:15])=[CH:10][C:11]([OH:14])=[C:12]([CH3:13])[C:7]=1[NH:6][CH2:4][C:3]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH:19]=[CH:20][C:2]=1[F:1]
Reactant: Cc1cc(O)c(C)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1F
Solvent: C1CCOC1
Product: Cc1cc(O)c(C)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 60 °C
Yield: 99.3 %

Procedure:
To a solution of 2-fluoro-N-(2-fluoro-5-hydroxy-3,6-dimethyl-phenyl)-5-(3-fluorophenyl)benzamide (230 mg, 0.62 mmol, 1.0 eq) in THF (3 mL) at 0° C. under N2 was added a solution of BH3 (1M in THF, 3.7 mL, 3.7 mmol, 6.0 eq) dropwise. The reaction mixture was heated at 60° C. overnight. After cooling, the reaction was quenched by addition of water and extracted with EtOAc. The organic extract was washed with aqueous NaHCO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (220 mg, 99%).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:55]([OH:57])=[O:56])[CH2:43][CH2:44][C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:40])[CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:27])[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:58]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:59]([C:71](ON1C(=O)CCC1=O)=[O:72])[CH2:60][C:61](=[O:70])[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.CCN(CC)CC.CS(C)=O>CN(C=O)C>[NH:58]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:59]([C:71]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:26]([NH:28][C@H:29]([C:39]([NH:41][C@H:42]([C:55]([OH:57])=[O:56])[CH2:43][CH2:44][C:45](=[O:54])[O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:40])[CH2:30][O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:27])[CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14])[C@@H:3]([CH3:12])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:72])[CH2:60][C:61](=[O:70])[O:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O

Procedure:
Boc-Thr(Bzl)-Ser(Bzl)-Ser(Bzl)-Glu(OBzl)-OH (54.5 g, 61.7 mmol) was treated with HCl in THF (1.5 liters; 4.1 N; 40 min) and worked up as usual to give HCl.H-Thr(Bzl)-Ser(Bzl)-Ser(Bzl)-Glu(OBzl)-OH (46.3 g, 56.6 mmol) as a white powder. It was then stirred in DMF (500 ml) with Boc-Asp(OBzl)-OSu (23.7 g, 56 mmol) at 0° for 2 hours in the presence of Et3N (16 ml). The mixture was further stirred at 25° for 15 hours during which time 7.4 ml more of Et3N was added. The product was worked up as usual and crystallized from CH2Cl2 and petroleum ether: yield, 50.35 g (82.7%); mp 111°-113°; [α]D25 =+7.21° (c 1, DMSO).
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].C([O-])(=O)C.[Na+].Cl.[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21].C(O)(=O)C>C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:21][C:9](=[O:10])[C@H:4]([CH2:5][C:6](=[O:7])[OH:8])[NH:3][CH:1]=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@H]1CC(=O)OC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC=O
Yield: 65 %

Procedure:
In 100.1 g of ethyl acetate, 14.3 g (0.1 mole) of N-formyl-L-aspartic anhydride was suspended, and 9.2 g (0.11 mole) of sodium acetate was added at -50°-0° C. with stirring, and 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride was further added at the same temperature. The mixture was reacted for 5 hours with stirring at the same temperature. Thereafter 14.3 g of acetic acid was added and stirred for an hour at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in a yield of 20.9 g (65.0% yield on L-phenylalanine methyl ester hydrochloride). The crystals obtained were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 99.0:1.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>C1COCC1.CN(C1C=CN=CC=1)C>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNS(=O)(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
To a solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.10 g, 0.26 mmol) in THF (5 ml) at room temperature was added 1.1 equivalent of trifluoromethylsulfonyl chloride loaded TFP resin, and DMAP (0.031 g, 0.26 mmol). The reaction was then stirred at room temperature for 15 hours and filtered. The remaining resin was then washed with THF (2×10 ml for 20 min), and then combined organic fractions were concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.02 g, 15%). 1H NMR (400 MHz, CD3OD) δ7.40-7.37 (m, 2H), 7.17 (d, J=10.9 Hz, 1H), 7.02-6.97 (m, 2H), 5.90-5.60 (br s, 1H), 5.14-5.12 (m, 1H), 4.28-4.25 (m, 2H), 1.88-1.84 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.95-0.93 (m, 2H), 0.67-0.64 (m, 2H). MS: Calcd.: 516. Found: [M+H]+ 517.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2C(=O)[N:16]([N:19]=[CH:20][CH:21](C)[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29][OH:30].[BH4-].[Li+].Cl>O1CCCC1.O>[CH:20]1([NH:19][N:16]2[C:29](=[O:30])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH2:21][CH2:22][CH2:8][CH2:7][CH2:6][CH2:11]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1NC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.06 g, 0.13 mmol) in tetrahydrofuran (4 mL) and methanol (0.011 mL, 0.26 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.10 mL, 0.2 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.35 (m, 4 H) 1.50 (m, 4 H) 1.64 (m, 3 H) 1.86 (m, 1 H) 2.56 (m, 1 H) 5.62 (d, J=2.94 Hz, 1 H) 7.12 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.09 Hz, 1 H) 7.26 (t, J=7.54 Hz, 1 H) 7.53 (m, 1 H) 7.64 (d, J=7.72 Hz, 1 H) 7.72 (d, J=5.15 Hz, 1 H) 15.92 (s, 1 H). MS (ESI−) m/z 457 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[CH3:20])=[CH:11][CH:10]=2)[N:7]=1.Cl>C(O)C>[CH3:20][C:16]1[N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[N:7]=[C:2]([OH:1])[C:3]4[CH2:24][NH:23][CH2:22][CH2:21][C:4]=4[N:5]=3)=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCNC3)cc1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
tert-Butyl 4-hydroxy-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (2.3 g, 5.44 mmol, Example 9d) was added to a solution of hydrogen chloride (10 mL, 5.44 mmol) in ethanol (20 mL). The solution was stirred at 75° C. for 30 min allowing the EtOH to evaporate. The solution was made basic with potassium carbonate (s) and EtOAc (20 mL) was added. After stirring 10 min the precipitated product was filtered off and dried to give 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (1.300 g, 74.1%). MS (ESI+)/(ESI−) m/z 323/321
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[CH2:19][N:20]([CH2:31][C:32]([O:34][CH3:35])=[O:33])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].[NH4+].[Cl-].Cl>CO>[CH3:35][O:34][C:32]([C:31]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:19][N:20]=1)[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8](=[O:11])[CH:9]=[CH:10]2)=[O:33]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)ccc(=O)n1Cc1ccccc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1ncc2c(ccc(=O)n2Cc2ccccc2)c1O
Reaction time: 16 h
Yield: 83.4 %

Procedure:
1-Benzyl-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2 g, 4.02 mmol) was dissolved in 60 mL of MeOH. NaOMe solution (3 mL, 12.5 mmol, 25 wt % in MeOH) was added and the mixture was stirred for 16 h. Saturated NH4Cl (100 mL) was added, followed by addition of 1M HCl until pH about 2. The resulting mixture was extracted several times with CH2Cl2. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 1.04 g of the title compound as a white solid. MS: (+) m/z 311.05 (M+1).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)C1C=CC=CC=1>[Pd]>[OH:13][C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[NH:14][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(N[C@@H]1CN(Cc2ccccc2)C[C@H]1O)c1ccccc1
Agent: [Pd]
Product: O=C(N[C@@H]1CNC[C@H]1O)c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of trans-N-(1-benzyl-4-hydroxy-3-pyrrolidinyl)benzamide and palladium-on-charcoal catalyst is hydrogenated at 60° C. for 4 hrs. to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:24]=[C:25]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][C:32]=2[CH3:41])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:8]([O:10][CH3:11])=[O:9].O.[OH-].[Li+].O.Cl>[Cl-].[Na+].O.O1CCOCC1>[F:1][C:2]([F:49])([F:50])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:24]=[C:25]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:32]=2[CH3:41])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(=O)OC)c2)c(C)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(-c2ccc(C(=O)O)cc2C)ccc1OC

Procedure:
Methyl 2″-{[[3,5-bis(trifluoromethyl)benzyl] (methoxycarbonyl)amino]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (34.7 mg, 0.0486 mmol), lithium hydroxide monohydrate (10 mg, 0.238 mmol), water (0.4 mL) and 1,4-dioxane (1 mL) were stirred at room temperature for 5.5 hours to complete the reaction. Crude mixture was acidified with HCl (aq, 1N, 6 mL). The resulting mixture was worked up with brine and extracted with ethyl acetate. The combined extracts were back-washed with water. The resulting organic layer was dried over Na2SO4, filtered and evaporated in vacuo to afford a clear oil. The resulting oil was purified on SiO2 to afford as a clear glass 2″-{[[3,5-bis(trifluoromethyl)benzyl] (methoxycarbonyl)amino]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=699.17; found=700.29 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.72 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.55-7.46 (m, 1.5H), 7.43-7.34 (m, 2.5H), 7.32-7.25 (m, 1H), 7.07-7.5 (m, 1H), 4.62-4.22 (m, 4H), 3.77 (s, 3H), 3.73 (d, J=17 Hz, 3H), 3.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:29][NH:30][O:31][CH3:32].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:30]([O:31][CH3:32])[CH3:29])=[O:13])=[CH:5]2
Reactant: CNOC
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a flask containing 5-chloroindole-2-carboxylic acid (8.33 g, 42.6 mmol) were added EDC (12.6 g, 63.9 mmol), HOBt (8.63 g, 63.9 mmol), N,O-dimethylhydroxylamine hydrochloride (6.23 g, 63.9 mmol) sequentially. N,N-Dimethylformamide (100 mL) was added, followed by DIEA (22.6 mL, 128 mmol), and the resulting solution was stirred at 40° C. for 18 h. The reaction mixture was allowed to cool to room temperature, then was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting amide was taken forward without further purification: LCMS B, tr=2.03 min, m/z 239.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.24 (dd, J=8.5, 2.0 Hz, 1H), 7.16 (s, 1H), 3.85 (s, 3H), 3.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:32])=O)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[C:33]([O:36]C(=O)C)(=[O:35])[CH3:34]>>[C:33]([O:36][CH2:32][S:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=2)=[CH:25][CH:26]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Product: CC(=O)OCSc1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reaction time: 5 h

Procedure:
To a solution of 5-(4-chloro-phenyl)-6-(4-methanesulfinyl-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (1.20 g, 2.60 mmol) in dry acetic anhydride (12 mL) sodium acetate (0.800 g, 9.76 mmol) is added and the resulting mixture is heated to reflux. After 5 h, the reaction mixture is concentrated. The crude product is purified by column chromatography (silica gel, 60-120 mesh) to afford (4-(5-(4-chlorophenyl)-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenylthio)methyl acetate.