Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][CH:36](OC)[O:37]C)=[O:33])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.O>C(=O)(O)[O-].[Na+]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH:34][CH2:35][CH:36]=[O:37])=[O:33])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(C(=O)NCC(OC)OC)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2csc3c(C(=O)NCC=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 70.3 %

Procedure:
4-Amino-N-(2,2-dimethoxyethyl)-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridine-7-carboxamide (100 mg, 0.18 mmol), trifluoroacetic acid (2 mL), and water (4 mL) were combined at ambient temperature for 2 hours. Mixture was diluted with a solution of saturated sodium bicarbonate (50 mL) and filtered to yield the title compound (65 mg, 70% yield): 1H NMR (DMSO, 400 MHz) δ 9.59 (s, 1H), 9.50 (s, 1H), 9.13 (m, 1H), 8.61 (s, 2H), 8.08 (d, 1H), 7.79 (s, 1H), 7.65 (dd, 2H), 7.32-7.35 (m, 2H), 7.25 (s, 1H), 7.10-7.16 (m, 2H), 4.16 (d, 2H), 4.04 (s, 3H), 3.92 (s, 3H); RP-HPLC (5% to 95% acetonitrile over 5 minutes, 1 ml/min, 254 nm, betasil HS 100 Å, C18, 5 μm, 50×2.1 column) Rt 3.54 min. MS: 531.0 MH+.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].C([O:10][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[N:16][N:17]=1)=O)C>>[CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:11]([C:13]1[S:14][C:15]([N:18]2[CH2:19][CH2:20][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23]2)=[N:16][N:17]=1)=[O:10]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: CC(C)CCCN
Product: CC(C)CCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-methylpentylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.045 g, yield 79%). 1H NMR (300 MHz, CDCl3) δ 7.73-7.7 (m, 1H), 7.64-7.5 (m, 2H), 7.34-7.32 (m, 1H), 7.06 (br., t, 1H), 4.09-3.8 (m, 1H), 3.93-3.81 (m, 1H), 3.75-3.6 (m, 2H), 3.56-3.48 (m, 2H), 3.43-3.29 (m, 4H), 1.63-1.48 (m, 3H), 1.46-1.16 (m, 2H), 0.85 (d, J=6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 174.5, 167.5, 158.2, 156.0, 133.9, 132.3, 129.6, 126.9, 126.8, 126.7, 125.3, 121.7, 49.5, 48.9, 45.9, 40.7, 39.9, 35.9, 27.7, 27.3, 22.4. MS (ES+) m/z 470 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)C(OCC1C=CC=CC=1)=O>CCOC(C)=O.CCO>[CH3:1][NH:2][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CN(CC1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 106.1 %

Procedure:
Using Deprotection Method A, 4-[(N-methyl)benzyloxycarbonylaminomethyl]-1-Boc-piperidine (0.30 g, 0.83 mmol) in EtOAc (5 mL) and EtOH (14 mL) afforded 201 mg (88%) of the title compound which was used without further purification.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([O:26]C(OCC)C)[CH2:17][CH2:18]2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2].Cl.O.C(=O)([O-])O.[Na+]>CC(C)=O>[C:1]([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:26])[CH2:17][CH2:18]2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CCOC(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)O[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.75 h
Yield: 97.1 %

Procedure:
iv)—A solution of (3β,20S)-3-[(1-ethoxyethyl)oxy]pregn-5-en-20-ol acetate (66.1 g) in acetone (1330 ml) was treated with a 4 M aqueous solution of hydrochloric acid (13.2 ml). The reaction mixture was stirred for 45 min. and subsequently poured into a mixture of water (3 l) and a saturated aqueous solution of sodium hydrogen carbonate (500 ml). The resulting precipitate was collected by filtration and then dissolved in dichloromethane. The filtrate was extracted with ethyl acetate. The dichloromethane and ethyl acetate solutions were washed with a saturated aqueous solution of sodium hydrogen carbonate and with brine, dried over sodium sulfate, and concentrated under reduced pressure to give (3β,20S)-pregn-5-ene-3,20-diol 20-acetate (compound 5; 53.5 g), which was used in the following step without further purification.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]1[CH2:15][N:14]([CH2:16][C:17]2[N:24]3[C:20]([S:21][C:22]([CH2:25][O:26][CH3:27])=[N:23]3)=[N:19][C:18]=2[Cl:28])[C:13](=[O:29])[CH2:12]1)C1C=CC=CC=1.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(N(CC)CC)C.O>FC(F)(F)C(O)=O.CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:37][C:36]1[CH:38]=[CH:39][C:33]([S:30]([O:8][CH2:9][CH2:10][CH:11]2[CH2:12][C:13](=[O:29])[N:14]([CH2:16][C:17]3[N:24]4[C:20]([S:21][C:22]([CH2:25][O:26][CH3:27])=[N:23]4)=[N:19][C:18]=3[Cl:28])[CH2:15]2)(=[O:32])=[O:31])=[CH:34][CH:35]=1
Reactant: COCc1nn2c(CN3CC(CCOCc4ccccc4)CC3=O)c(Cl)nc2s1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCc1nn2c(CN3CC(CCOS(=O)(=O)c4ccc(C)cc4)CC3=O)c(Cl)nc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
4-[2-(benzyloxy)ethyl]-1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one a37 (300 mg, 0.69 mmol, 1 eq) is heated at 60° C. for 3 hours in trifluoroacetic acid (3 ml). The crude 1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2-hydroxyethyl)pyrrolidin-2-one a38 is obtained after cooling and evaporation of the volatiles under reduced pressure. Dichloromethane (10 ml) is added to the residue, the mixture is cooled to 0° C., then tosyl chloride (158 mg, 0.828 mmol, 1.2 eq), triethyl amine (0.48 ml, 3.45 mmol, 5 eq) and 4-dimethylamino-pyridine (8 mg, 10 mol %,) are added at 0° C. The reaction is kept for 1 h at 0° C., then warmed up to room temperature and stirring is pursued for 2 days. After hydrolysis (H2O, 10 ml) and extraction with CH2Cl2 (4×10 ml), the cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The residue is purified by flash chromatography over silicagel (eluent: CH2Cl2/MeOH 97:3) to afford 308 mg of 2-(1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-5-oxopyrrolidin-3-yl)ethyl 4-methylbenzenesulfonate a39.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.Cl[S:21]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28])(=[O:23])=[O:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([OH:29])=[O:28])(=[O:23])=[O:22])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: O=C(O)c1cccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 3-(chlorosulfonyl)benzoic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][O:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=N.[ClH:22].N([O-])=O.[Na+].[OH-].[Na+]>O>[CH3:1][C:2]([CH3:21])([CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:3][O:4][N:5]=[C:6]([Cl:22])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cl
Reactant: CC(C)(CONC(=N)c1cccnc1)CN1CCCCC1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CON=C(Cl)c1cccnc1)CN1CCCCC1
Reaction time: 2 h

Procedure:
To a solution containing 2.23 g (7.63 mmoles) of N-(2,2-dimethyl-3-piperidinopropoxy)-3-pyridinecarboxamidine in 30 ml of a 1:1 mixture of concentrated hydrochloric acid and water, 2.63 g (38.2 mmoles) of sodium nitrite dissolved in 10 ml of water are dropwise added at 0° C. The reaction mixture is stirred at the same temperature for an additional 2 hours, then the pH value is adjusted to 12 by adding 2N sodium hydroxide solution, and the mixture is extracted twice with 30 ml of chloroform each. The organic phase is washed with 30 ml of water, dried over sodium sulfate, filtered and evaporated. The oily residue (1.83 g) is purified by column chromatography to give the title compound as a pale yellow oil in a yield of 1.62 g (68.5%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23]>C1COCC1>[CH3:1][N:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23])[CH3:3]
Reactant: CNC
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ccc(CBr)cc12
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2oc(-c3ccc(O)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68 %

Procedure:
Dimethylamine (1M solution in THF, 1.2 mL) was added to 6-bromomethyl-2-(4-hydroxyphenyl)chromen-4-one (206 mg, 0.62 mmol) dissolved in dry THF (10 mL). The reaction mixture was stirred at rt for 17 hr. Most of the solvent was then removed in vacuo and the yellowish residue was suspended in 20 mL of water. The resulting suspension was stirred at rt for 30 min and the solid was removed by filtration, washed with water, ether, and air-dried to afford 6-((dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one (125 mg, 68%). MS (ES) m/z: 296.98 (M+1), 295.97 (M); Mp. 99-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH3:15])=[CH:10][C:11]([O:13][CH3:14])=[O:12].[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(O)(=O)C.N1C2C=CC=CC=2N=CC(C(OC)=O)=C1>O1CCCC1.CC(C)=O>[CH3:15][C:9]1[NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[C:17]([F:16])([F:26])[F:27])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COC(=O)C=C(C)Nc1ccccc1N
Agent: COC(=O)C1=CNc2ccccc2N=C1
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)Nc2ccccc2NC1c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-[(2-aminophenyl)amino]-2-butenoic acid, methyl ester (2.50 g., 12.0 mmole) in anhydrous tetrahydrofuran (12 ml.) is treated with 2-(trifluoromethyl)benzaldehyde (1.74 g., 10.0 mmole) and acetic acid (0.2 ml.). The resulting reaction mixture is stirred at room temperature under argon for 24 hours. The solvent is removed and the resulting yellow solid is triturated with isopropyl ether to give 3.27 g. of an off-white product. Recrystallization from dichloromethane-isopropyl ether gives 2.39 g. of 2,5-dihydro-4-methyl-2-2-(trifluoromethyl)phenyl]-1H-1,5-benzodiazepine-3-carboxylic acid, methyl ester; m.p. 190°-192°. TLC (silica gel; acetone:hexanes, 35:65) Rf =0.47.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH3:26])[NH:21]1.Cl>C(Cl)Cl>[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH3:26])[N:21]1[C:2]([Cl:1])=[O:4]
Reactant: C[C@@H]1CCC[C@H](C)N1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CCC[C@H](C)N1C(=O)Cl
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 256.2 %

Procedure:
To a solution of triphosgene (20.8 g, 70.0 mmol) in DCM (400 mL) at 5° C. was added pyridine (16.2 mL, 200 mmol) dropwise over 10 min, maintaining the temperature below 10° C. The solution was then stirred between 5-10° C. for 1 h, then cis-2,6-dimethyl piperidine (CAS: 766-17-6, 27.0 mL, 200 mmol) was added dropwise over 10 min and the resulting red solution stirred at RT for 4 days (reaction complete within <4 h). The solution was cooled to 3° C., then a pre-cooled (3° C.) 1M aqueous HCl solution (400 mL) was added and the mixture stirred at 5° C. for 30 min. The mixture was separated and the aqueous layer was extracted with DCM (200 mL), then the combined organic extracts passed through a hydrophobic fit and concentrated under vacuum affording Intermediate 3a as a red oil (31.5 g, 90%). 1H NMR (300 MHz, CDCl3): 1.30 (6H, d, J=7.09 Hz), 1.49-1.87 (6H, m), 4.46-4.56 (2H, m).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:15]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:26]=2[CH3:27])=[O:21])[CH2:16][CH2:17][CH3:18])[CH:14]=1)(=[O:8])=[O:7].[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][CH2:4][CH2:5][S:6]([C:9]1[CH:14]=[C:13]([CH:15]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[C:26]=2[CH3:27])=[O:21])[CH2:16][CH2:17][CH3:18])[CH:12]=[N:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(S(=O)(=O)CCC(=O)OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(NC(=O)c1cnn(-c2ccc(Cl)cc2)c1C)c1cncc(S(=O)(=O)CCCO)c1
Temperature: 70 °C
Yield: 16.3 %

Procedure:
A solution of 3-[5-(1-{[1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-butyl)-pyridine-3-sulfonyl]-propionic acid methyl ester (51 mg, 0.10 mmol) in THF (2.5 mL) is treated lithium borohydride (13 mg, 0.59 mmol) and heated at 70° C. for 1 hour. After cooling to room temperature, the reaction is quenched by slow addition of 10 mL of water and extracted with EtOAc (2×25 mL). The combined organic layers are washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (eluted with 50 to 100% EtOAc/hexanes) followed by preparative reverse phase HPLC (eluted with 5 to 95% CH3CN/H2O and 0.1% TFA as additive) affords 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid {1-[5-(3-hydroxy-propane-1-sulfonyl)-pyridin-3-yl]-butyl}-amide (8.0 mg, 17%).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=2[CH2:20][O:21][CH3:22])[CH:7]=[CH:8][CH:9]=1>CCO>[F:3][C:4]1[C:5]([CH3:23])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[CH2:20][O:21][CH3:22])[CH:7]=[CH:8][CH:9]=1
Reactant: COCc1cc(C(=O)OC)ccc1-c1cccc(F)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1-c1cccc(F)c1C
Temperature: 60 °C

Procedure:
A 5N aqueous solution of NaOH (5.0 mL, 25 mmol) was added into a solution of methyl 3′-fluoro-2-(methoxymethyl)-2′-methylbiphenyl-4-carboxylate (4.85 g, 16.8 mmol) in EtOH (50 mL). The reaction mixture was heated at 60° C. for 1 hour, and then was concentrated under reduced pressure. The residue was taken up with MTBE (100 mL), water (50 mL) and a 5N aqueous solution of HCl (6 mL). The layers were separated and the organic layer was washed with water (50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (50 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by crystallization from a mixture of MTBE and pentane, the title compound was obtained as a white powder (3.85 g, 83%). HPLC (Method A), Rt: 4.2 min (purity: 99.8%). UPLC/MS, M−(ESI): 273.0. 1H NMR (DMSO-d6, 300 MHz) δ 13.06 (s, 1H), 8.09 (d, J=1.7 Hz, 1H), 7.92 (dd, J=7.9, 1.7 Hz, 1H), 7.35-7.17 (m, 3H), 6.97 (d, J=7.6 Hz, 1H), 4.13 (s, 2H), 3.18 (s, 3H), 1.90 (d, J=2.3 Hz, 3H).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2O.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[N:13]1[C:9](=[O:19])[C:10]2[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]1=[O:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O[C@H]1C[C@H]2CC[C@@H]1C2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2CC[C@@H]1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
To a solution of (1R,2S,4S)-bicyclo[2.2.1]heptane-2-ol (1.0 g) in tetrahydrofuran (10 ml) were added phthalimide (1.4 g) and triphenylphosphine (2.6 g), and diethylazodicarboxylate (1.5 ml) dropwise under ice cooling. The mixture was warmed to ambient temperature and stirred for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate)=100:0 to 95:5) to obtain 2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-1H-isoindole-1,3(2H)-dione (1.4 g) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][N:6]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]2[NH:31][C:30](=[O:32])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]2=[O:37])=[CH:20][C:19]=1[O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[S:7]([NH:10]C(OC(C)(C)C)=O)(=[O:9])=[O:8])[CH3:2]>C(Cl)Cl.FC(C(O)=O)(F)F.C([SiH](CC)CC)C>[CH2:1]([O:3][C:4](=[O:46])[CH2:5][N:6]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]2[NH:31][C:30](=[O:32])[C:29]3[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=3[NH:27][C:26]2=[O:37])=[CH:20][C:19]=1[O:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[S:7]([NH2:10])(=[O:8])=[O:9])[CH3:2]
Reactant: CCOC(=O)CN(c1ccc(CC2NC(=O)c3ccccc3NC2=O)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN(c1ccc(CC2NC(=O)c3ccccc3NC2=O)cc1OCc1ccccc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title M compound, N-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[t-butyloxycarbonylaminosulfonyl]-amino-acetic acid ethyl ester (124 mg, 0.19 mmol) is dissolved in CH2Cl2-TFA-triethylsilane (2.5:7:0.5, 1.5 mL) and the solution is stirred at RT for 1 h and evaporated. The residue is dissolved in EtOAc and the solution is washed twice with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and evaporated to give N-[2-benzyloxy-4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[1,4]diazepin-3-ylmethyl)-phenyl]-N-[aminosulfonyl]-amino-acetic acid ethyl ester as a foam: [M+1]+=553.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[C:20]3[CH2:19][C:18]([O:21]CC)=[CH:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1=CCc2cccc(Nc3ncc(C(C)(C)C)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: CC(C)(C)c1cnc(Nc2cccc3c2CC(=O)CC3)o1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 17B for the product of Example 1H.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[Li]CCCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1.Cl>[OH:20][B:21]([OH:22])[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To solution of 3-Bromo-4-fluoro-benzoic acid (1.0 eq) in THF (0.2M) at −78° C. was added n-BuLi (2.5M in Hex; 2.2 eq). The resulting mixture was stirred at −78° C. for 15 min then tri-isopropoxy borane (2.2 eq). The final mixture was stirred 1 h at −78° C. then 4 h at room temperature and finally poured in HCl (10%). After stirring for 12 h, THP was evaporated and the residual mixture was diluted with EtOAc. The organic extract was washed with HCl (10%), brine, dried over MgSO4, filtered and concentrated. The residue was suspended in EtOAc, stirred for 4 h and the desired compound was isolated by filtration.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH2:20])[C:15]([C:21]([OH:23])=[O:22])=[C:14]2[CH2:24][CH2:25][CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:35]>O1CCOCC1.C(Cl)Cl>[ClH:35].[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([NH2:20])[C:15]([C:21]([OH:23])=[O:22])=[C:14]2[CH2:24][CH2:25][CH2:26][NH2:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)n(N)c2ccc(C(=O)OCc3ccccc3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCc1c(C(=O)O)n(N)c2ccc(C(=O)OCc3ccccc3)cc12
Reaction time: 0.75 h

Procedure:
5-(Benzyloxycarbonyl)-amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid (72 mg) was dissolved in 5 mL of 4 N HCl in dioxane. Within 10 min a white crystalline solid had formed. The mixture was stirred for 45 min at which time the reaction was diluted with 10 mL of methylene chloride. The filtrate was removed with a filter-tipped cannula and the solid was washed 3×10 mL of methylene chloride and dried, providing the title compound; MS, electrospray, 369 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH:9]2[CH2:18][CH2:17][C:12]3([O:16]CCO3)[CH2:11][CH2:10]2)[C:6]([CH3:19])=[CH:5][C:3]=1[NH2:4].Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[C:24]([C:34]([F:37])([F:36])[F:35])=[CH:23][N:22]=1.Cl.CO>CC(O)C>[CH3:19][C:6]1[CH:5]=[C:3]([NH:4][C:21]2[N:26]=[C:25]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[C:24]([C:34]([F:35])([F:37])[F:36])=[CH:23][N:22]=2)[C:2]([CH3:1])=[CH:8][C:7]=1[CH:9]1[CH2:10][CH2:11][C:12](=[O:16])[CH2:17][CH2:18]1
Reactant: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Reactant: Cc1cc(C2CCC3(CC2)OCCO3)c(C)cc1N
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2C(F)(F)F)n[nH]1
Temperature: 125 °C

Procedure:
A mixture of 2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline (111.3 mg, 0.43 mmol), 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine (119.6 mg, 0.43 mmol), HCl (4 N in water, 0.11 mL, 0.43 mmol) in i-PrOH (4.0 mL) was heated at 125° C. in an oil bath over night. The reaction mixture was concentrated in vacuo. The crude product was dissolved in THF (2 mL), MeOH (1 mL) and HCl (4N in water, 0.11 mL, 0.43 mmol), and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo, followed by purification by silica chromatography (0-100% EtOAc in hexanes gradient) to afford 4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone; ESMS m/z 459.2 (M+H+).