Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24](Cl)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([C:48]4[CH:49]=[CH:50][C:45]([C:43]([O:42][CH3:41])=[O:44])=[CH:46][CH:47]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(C)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 72.8 %

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate (0.8 g, 1.63 mmol), K2CO3 (0.56 g, 4 mmol), Pd(PPh3)4 (0.28 g, 0.24 mmol) were dissolved in dioxane/water (20:1), 4-(methoxycarbonyl)phenylboronic acid (0.38 g, 2.1 mmol) was added the mixture was heated to 100° C. for 3 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography over silica gel using 30% EtOAc/hexanes as eluent to give the desired product (0.7 g). 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 8.43 (d, J=8.0 Hz, 2H), 8.10 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.49 (s, 2H), 2.68 (m, 4H), 2.50 (s, 3H), 2.33 (m, 4H), 1.91 (t, J=6.8 Hz, 3H), 1.39 (s, 9H); MS m/z 590.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:21])[C:10]1=[NH:22].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCCl>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=1[N:11]1[CH2:12][CH2:13][N:9]([C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:10]1=[N:22][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=N
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=NC(=O)c1ccccc1
Yield: 74 %

Procedure:
A mixture of 1.0 g (3.4 mmoles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine, prepared as described in Example 1, Method (a), 10 ml of 1,2-dichloroethane, 0.33 ml (0.32 g, 4.0 mmole) of dry pyridine and 0.46 ml (0.56 g, 4.0 mmoles) of benzoyl chloride is heated on a steam bath for 2 hours. The cooled mixture is washed thrice with 10 ml of water each, thrice with 10 ml of 10% aqueous sodium hydrogencarbonate solution each, and again thrice with 10 ml of water each, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. 1.0 g (74.1%) of crude 1,3-bis(2',6'-dimethylphenyl)-2-benzoylimino-imidazolidine are obtained. After recrystallization from aqueous methanol the product melts at 176°-178° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=1)[NH:23][CH2:22][CH2:21]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(CC)CC>C1COCC1>[CH2:10]([O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=1)[N:23]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:22][CH2:21]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(COc2ccc3c(c2)CCNC3c2ccc(OCCN3CCCC3)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCc2cc(OCc3ccccc3)ccc2C1c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 189.8 %

Procedure:
Benzoyl chloride (0.013 g, 0.09 mmol) was added to a solution of 6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.040 g, 0.09 mmol) and Et3N (0.026 ml, 0.19 mmol) in anhydrous THF (10 ml) at rt under N2. The resulting suspension was stirred at rt for 20 hr, then evaporated in vacuo to give 0.091 g of white solid. Purification by flash chromatography, eluting with EtOAc: MeOH (6:4) gave 0.049 g (98% yield) of white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>CC(O)=O>[O:17]=[C:8]1[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6](=[O:23])[C:5]2[C:10](=[CH:11][C:12]([C:13]([F:15])([F:16])[F:14])=[C:3]([CH2:2][N:1]3[CH:26]=[CH:30][CH:29]=[CH:28]3)[CH:4]=2)[NH:9]1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(Cn3cccc3)cc2c1=O
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (100 mg, 0.28 mmol) in conc. CH3CO2H (8 mL) was added 2,5-dimethoxytetrahydrofurane (41.3 μL, 0.31 mmol) and the reaction mixture was stirred for 20 min at reflux temperature. Subsequently, the solvent was evaporated and the crude brown residue was recrystallized from EtOAc/cyclohexane to yield N-(2,4-dioxo-6-pyrrol-1-ylmethyl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (108 mg, 0.27 mmol, 95%) as a light-brown solid. 1H-NMR (DMSO-d6, 400 MHz) 3.12 ppm (s, 3H, SO2—CH3); LC-MS rt=3.757 mn; MS: m/z 402.9 [M+H]+ Column: SunFireC18, 4.6*50 mn, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: C([O:9][CH2:10][C:11]([CH3:33])([CH3:32])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[C:23]([C:25]([O:27]CC)=[O:26])[CH:22]=[N:21]2)=[CH:16][C:15]=1[C:30]#[N:31])(=O)C1C=CC=CC=1.[OH-].[Na+].O.Cl>C(O)C>[C:30]([C:15]1[CH:16]=[C:17]([N:20]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[CH:22]=[N:21]2)[CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:11]([CH3:33])([CH3:32])[CH2:10][OH:9])#[N:31]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)COC(=O)c3ccccc3)c(C#N)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CO)COc1ccc(-n2cc(C(=O)O)cn2)cc1C#N
Temperature: 50 °C
Yield: 14.7 %

Procedure:
To a solution (20 ml) of ethyl 1-(4-(3-benzoyloxy-2,2-di methylpropoxy)-3-cyanophenyl) pyrazole-4-carboxylate (2.89 g) obtained in Example 37 in ethanol was added 1 N aqueous sodium hydroxide solution (14.2 ml) with stirring, and the mixture was heated at 50° C. for 3 hours. After the completion of the reaction, the reaction mixture was poured into water and neutralized with 1 N hydrochloric acid (15 ml). The precipitated crystals were recrystallized from ethyl acetate to give 0.3 g of 1-(3-cyano-4-(2,2-dimethyl 3-hydroxypropoxy)phenyl)pyrazole-4-carboxylic acid, melting point 188-190° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Temperature: 50 °C
Yield: 51.5 %

Procedure:
Add a solution of N-Boc-4-hydroxypiperidine (3.0 g, 14.9 mmol) in DMF (5 mL) to a suspension of sodium hydride (894 mg, 22.4 mmol) in DMF (17 mL). Stir the reaction mixture while heating at 50° C. for 45 min. Then add a solution of 4-fluoro-benzonitrile (2.16 g, 17.9 mmol) in DMF (5 mL). Stir and heat at 50° C. for 2 h. Let cool to room temperature and quench with water (0.5 mL). Evaporate DMF. Redissolved the resulting residue in EtOAc/hexanes (2/1, 20 mL) and wash with water (3×15 mL). Dry the organic layer over magnesium sulfate, filter and concentrate. Purify by chromatography (EtOAc/hexanes 20% and EtOAc/hexanes 10%) to yield the title compound (2.32 g, 52%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)=[CH:39][CH:38]=1>>[CH:45]1([CH2:44][O:43][C:40]2[CH:39]=[CH:38][C:37]([CH2:36][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]4[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=4[C:22]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]4)=[O:23])=[CH:4][CH:3]=3)=[CH:42][CH:41]=2)[CH2:46][CH2:47]1
Reactant: ClCc1ccc(OCC2CC2)cc1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(OCC4CC4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 4-[3-(4-{[4-(cyclopropylmethoxy)benzyl]oxy}phenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-(cyclopropylmethoxy)benzene.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:13])[CH:5]=[CH:6][C:7]2=[O:12].[Br:14]Br>>[CH:10]1[CH:11]=[C:2]([OH:1])[C:3]2[C:4]([C:5]([Br:14])=[CH:6][C:7](=[O:12])[C:8]=2[CH:9]=1)=[O:13]
Reactant: BrBr
Reactant: O=C1C=CC(=O)c2c(O)cccc21
Product: O=C1C=C(Br)C(=O)c2c(O)cccc21

Procedure:
Step 1 in the above Scheme B may be, for example, carried out according to Tietze, et al., Chem. Eur. J., 2007, 13, 9939-9947. For example, to 5-hydroxynaphthalene-1,4-dione dissolved in an appropriate solvent is added bromine to give 3-bromojuglone in Step 1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:11][O:9][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1nccnc1C(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1nccnc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-pyrazine-2-carboxylic acid (4.7 g) in toluene (70 ml) and methanol (30 ml) at ambient temperature was added drop wise (trimethylsilyl)diazomethane (2M in diethyl ether) (26 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated and purified by passing through a pad of silica and eluting with 30% v/v ethyl acetate in iso-hexane to give 3-methyl-pyrazine-2-carboxylic acid methyl ester (3.10 g). 1H-NMR (400 MHz, CDCl3): 8.63 (d, 1H), 8.53 (d, 1H), 4.02 (s, 3H), 2.87 (s, 3H) ppm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:27]([O:29]CC)=O)[C:22]([O:24]CC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:27](=[O:29])[CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])=[O:24]
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Reactant: NCCCCN
Product: NCCCCNC(=O)C(CCCCCCOCc1ccccc1)C(=O)NCCCCN
Temperature: 90 °C

Procedure:
To a large excess of 1,4-diaminobutane (85 g, 0.964 mol) at 90° C. under argon was slowly added (over 2 hours) B2 (10.50 g, 0.030 mol). The solution was heated at 90° C. overnight and the excess diamine distilled off under reduced pressure (0.1 mBar, 28° C.) to quantitatively yield the title compound as a pale yellow low melting point solid. C24H42N4O3 requires 434. Found DCl: M++1 435. I.R. 1664 cm−1 (CO2). δH (CDCl3) 1.15-1.40 (10H, br m, (CH2)3CH2CH, NH2), 1.40-1.60 (10H, br m, (CH2)2CH2NH2, CH2CH2O), 1.76 (2H, q, CH2CH), 2.63 (4H, t, CH2NH2), 2.93 (2H, t, CH2CH), 3.16 (4H, q, CH2NH), 3.37 (2H, t, CH2OCH2Ph), 4.42 (2H, s, CH2Ph), 7.26 (5H, m, Ph), 7.61 (2H, t, CONH). δC (CDCl3) 25.7 (1C, CH2(CH2)2CH), 26.6 (2C, CH2CH2NH2), 28.8, 29.4 (2C, CH2CH2CH, CH2CH2O), 30.6 (2C, CH2CH2NH), 32.7 (1C, CH2CH), 39.0 (2C, CH2NHCO), 41.4 (2C, CH2NH2), 54.7 (1C, CHCO), 70.1, 72.6 (2C, CH2OCH2), 127.2 (1C, CH(CH)2C), 127.3 (2C, CHC), 128.0 (2C, CHCHC), 138.5 (1C, CCH2O), 171.0 (2C, CONH).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[CH:12][C:11]=1[F:28])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:28][C:11]1[CH:12]=[C:13]([O:16][C@@H:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][N:30]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@@H]3CCC[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@@H]1CCC[C@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 90.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (150 mg, 0.26 mmol) prepared in Example 128b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (98.0 mg, 89%) as a colorless solid.
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[CH3:28][CH:29]([OH:31])[CH3:30].[H-].[Na+].Cl>O1CCCC1>[CH3:28][CH:29]([O:31][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)[CH3:30]
Reactant: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
2-(Methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (100 mg) was suspended in tetrahydrofuran (4 ml), 2-propanol (77 μl) was added thereto, and then sodium hydride (25.0 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 min, and then at room temperature for 15 min. To the reaction mixture was added 0.5M hydrochloric acid (3 ml), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (35.4 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[C:5]([CH3:16])[O:4][N:3]=1.C(O[CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:15][CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[C:5]([CH3:16])[O:4][N:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(N)cc1-c1c(C)noc1C
Product: CCOC(=O)C(=CNc1ccc(OC)c(-c2c(C)noc2C)c1)C(=O)OCC
Temperature: 130 °C

Procedure:
[3-(3,5-Dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amine (for a preparation see Intermediate 60, 27.4 g, 126 mmol) was dissolved in diethyl [(ethyloxy)methylidene]propanedioate (27.1 g, 126 mmol) and heated to 130° C. The solution was heated for 1 h, then cooled to room temperature and reduced to dryness in vacuo to give diethyl ({[3-(3,5-dimethyl-4-isoxazolyl)-4-(methyloxy)phenyl]amino}methylidene)propanedioate (50.1 g), which after standing overnight became as a brown crystalline solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12]1)=[O:10])(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH2:7][CH:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([OH:17])[CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)N1C[C@H](O)[C@@H](O)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(Cc1ccccc1)C(=O)N1C[C@H](O)[C@@H](O)C1

Procedure:
(3S,4S)-[1-Benzyl-2-(3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (360 mg, 1.00 mmol) was dissolved in 4 M HCl-dioxane (4 ml) at 25° C. for 3 hours. The mixture was concentrated and the resulting yellow solid triturated with ether and dried. Yield 304 mg, 103%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[N:5]2[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[NH:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][OH:35]>C(#N)C>[CH3:14][C:10]1[CH:9]=[C:8]([C:6]2[N:5]3[N:15]=[C:16]([CH3:19])[C:17]([I:18])=[C:4]3[N:3]=[C:2]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH2:34][OH:35])[CH:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1cccc(-c2cc(Cl)nc3c(I)c(C)nn23)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(-c2cc(N3CCC[C@H]3CO)nc3c(I)c(C)nn23)c1
Yield: 53.1 %

Procedure:
5-Chloro-7-(3-methylphenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (580 mg), DIPEA (0.4 mL) and (S)-2-pyrrolidinemethanol (400 mg) are stirred at 90° C. in an acetonitrile (60 mL) solvent for 6 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is purified by column chromatography to yield the target compound (360 mg). 1H NMR (CDCl3, 300 MHz): δ 7.67 (m, 2H), 7.40 (m, 2H), 7.27 (s, 1H), 6.10 (s, 1H), 4.48 (br, 1H), 3.88-3.55 (m, 4H), 2.44 (s, 3H), 2.38 (s, 3H), 2.08-1.97 (m, 3H), 1.76 (m, 1H).
Reaction SMILES: C(Cl)Cl.C(O)(C(F)(F)F)=O.C(OC([N:18]=[C:19]([N:21](C(OC(C)(C)C)=O)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:52])[CH2:27][C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[C:30]([NH:36][CH2:37][C:38]([F:50])([F:49])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45]([CH3:48])(=[O:47])=[O:46])[C:29]=1[F:51])[NH2:20])=O)(C)(C)C>>[C:19]([NH:21][O:22][CH2:23][CH2:24][NH:25][C:26](=[O:52])[CH2:27][C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[C:30]([NH:36][CH2:37][C:38]([F:49])([F:50])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[S:45]([CH3:48])(=[O:47])=[O:46])[C:29]=1[F:51])(=[NH:18])[NH2:20]
Reactant: CC(C)(C)OC(=O)N=C(N)N(OCCNC(=O)Cc1c(C#N)ccc(NCC(F)(F)c2ccccc2S(C)(=O)=O)c1F)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1C(F)(F)CNc1ccc(C#N)c(CC(=O)NCCONC(=N)N)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A solution of 3:1 CH2Cl2/TFA (0.8 mL) was added to N-[2-(N′,N″-bis(tert-butoxycarbonyl)amidinoaminooxy)ethyl]-2-{3-[(2,2-difluoro-2-(2 methanesulfonylphenyl)ethyl)amino]-6-cyano-2-fluorophenyl}acetamide (34.8 mg, 0.049 mmol)(prepared essentially as described in Example 2h), and the reaction mixture was stirred at room temperature for 3 h. After evaporating the solvents, the residue was subjected to flash chromatography (DCM/MeOH saturated with gaseous NH3; 95:5→90:10) to yield 18.4 mg (74%) of the title compound as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.24 (m, 1H), 7.74 (m, 3H), 7.20 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.87 (t, J=8.7 Hz, 1H), 4.24 (t, J=14.2 Hz, 2H), 3.80 (t, J=5.2 Hz, 2H), 3.72 (d, J=1.9 Hz, 2H), 3.43 (t, J=5.5 Hz, 2H), 3.27 (s, 3H). LC/MS (m/z) [M+1]+ 513.4 (calculated for C21H24F3N6O4S, 513.5).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[N:10]=2)[CH2:4][O:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(Cl)Cl>CN(C=O)C>[CH3:1][C:2]1([CH3:18])[O:7][CH2:6][CH:5]([NH:8][C:9]2[C:14]([NH:15][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[N:10]=2)[CH2:4][O:3]1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(N)c(NC2COC(C)(C)OC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OC)nc1NC1COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Crude N2-(2,2-dimethyl-1,3-dioxan-5-yl)-6-(methyloxy)-2,3-pyridinediamine (123.6 mmol) was dissolved in anhydrous DMF (500 ml) under argon and anhydrous K2CO3 (37.56 g) was added, followed by ethyl bromoacetate (12.31 ml). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting reddish-brown slurry was partitioned between DCM (1.2 L) and water (300 ml). The organic phase was separated and washed with water (300 ml), dried over Na2SO4, filtered and evaporated under reduced pressure to give a dark red oil, this was taken up in a minimum of DCM and purified by column chromatography on silica (eluted with 5%-60% EtOAc in petroleum ether (40-60°)). Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as a dark orange oil (35.42 g, 84%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1(C(O)=O)[C:18](=[O:19])[N:8]2[C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][C@H:5]1[C:18](=[O:19])[N:8]2[C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][CH2:11][C@@H:7]2[CH2:6]1
Reactant: O=C(O)C1(CCCCl)C[C@H]2CO[C@H](c3ccccc3)N2C1=O
Solvent: Cc1ccccc1
Product: O=C1[C@H](CCCCl)C[C@H]2CO[C@H](c3ccccc3)N12
Temperature: 120 °C
Yield: 94.5 %

Procedure:
The (3R,7aS)-6-(3-chloropropyl)-5-oxo-3-phenyl-hexahydropyrrolo[1,2-c]oxazole-6-carboxylic acid (32.65 g, 0.101 mol) was slurried in 300 mL of anhydrous toluene. The temperature of the mixture was raised to 120° C. over a ˜1 h period, and maintained at 120° C. for 2 h. After this time LC/MS analysis showed formation of the desired amide. The mixture was cooled to ambient temperature and transferred to a separatory funnel. The mixture was washed with 100 mL of half-saturated NaHCO3 solution and brine. During this process some insoluble material formed at the interface. This material was discarded. The toluene solution was stirred with 5 g of activated carbon (Norit, neutral) for 1 h, then filtered through a pad of Celite and evaporated. The amber syrup was placed on the vacuum line overnight. This afforded 26.7 g (94% yield) of (3R,6R,7aS)-6-(3-chloropropyl)-3-phenyl-dihydropyrrolo[1,2-c]oxazol-5(1H, 3H, 6H)-one.