Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])[NH2:6].C=O.[C:23]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[CH3:23][NH:6][C:5]1[CH:7]=[CH:8][C:9]([N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])=[C:3]([CH3:2])[CH:4]=1
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccccc2C1=O
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CNc1ccc(N2C(=O)c3ccccc3C2=O)c(C)c1

Procedure:
To a stirred solution of 1.4 g of the product aniline of Example 31 and 2.5 ml of 37% aqueous formaldehyde in 19 ml of acetonitrile was added in portions 0.62 g of sodium cyanoborohydride. After twenty minutes the solution was adjusted to pH 7 with glacial acetic acid and stirred for another hour. Ice was added, acetonitrile was removed in vacuo, and the mixture was partitioned between water and dichloromethane. The organic layer was dried over potassium carbonate, filtered, and concentrated to an oil which was chromatographed on a silica gel column using dichloromethane as eluent. Fractions containing the title compound were concentrated to give a solid, m.p. 159°-161°. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][CH2:31][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[O:38][CH3:37])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: COc1ccccc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1OC
Yield: 98.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, (2-methoxyphenyl)methanol (58 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (148 mg, yield 100%).
Reaction SMILES: C1(N2CCC([NH:9][C:10]([C:12]3[S:13][C:14]([S:20][C:21]4[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=4[Cl:28])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=3)=[O:11])C2)CC1.Cl.[N:30]1([C:39](=[NH:41])[NH2:40])[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38]C=2N=N1>>[C:39]([N:30]1[CH2:34][CH2:35][CH:36]([NH:9][C:10]([C:12]2[S:13][C:14]([S:20][C:21]3[C:22]([Cl:28])=[CH:23][N:24]=[CH:25][C:26]=3[Cl:27])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=2)=[O:11])[CH2:37][CH2:38]1)(=[NH:41])[NH2:40]
Reactant: O=C(NC1CCN(C2CC2)C1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: N=C(N)n1nnc2ccccc21
Agent: Cl
Product: N=C(N)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 236 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(piperidin-4-yl)thiophene-2-carboxamide (0.2 g, 0.43 mmol) from example 198 and 1H-benzo[d][1,2,3]triazole-1-carboximidamide HCl salt (0.17 g, 0.85 mmol) from example 236 step A. The titled product was afforded as a solid (15 mg, 7% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.72 (1H, m), 8.47 (1H, s), 7.37 (4H, m), 3.98 (1H, m), 3.83 (2H, m), 3.17 (2H, m), 1.86 (2H, m), 1.44 (2H, m). MS m/z: 475.11, 477.13 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][NH:24][CH3:25].C(N(C(C)C)C(C)C)C>CN(C)C=O.CN(C1C=CN=CC=1)C.ClCCl>[F:18][C:19]([F:33])([F:34])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][N:24]([CH3:25])[C:6](=[O:8])[C:5]1[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.6 %

Procedure:
To a solution of 300 mg (1.12 mmol) 6-chloro-4-(2-chloro-phenyl)-nicotinic acid (Example 24, step e)) in 12 ml dichloromethane 0.15 ml (1.7 mmol) oxalyl chloride and one drop of N,N-dimethylformamide were added at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated in vactio. The residue was redissolved in 6 ml dichloromethane and added dropwise to a solution of 432 mg (1.68 mmol) (3,5-bis-trifluoromethyl-benzyl)-methyl-amine, 0.39 ml (2.2 mmol) N-ethyldiisopropylamine and 7 mg (0.06 mmol) 4-(N,N-dimethylamino)pyridine in 6 ml dichloromethane at 0° C. After completed addition the reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was diluted with dichloromethane and washed with two portions of 1 M aqueous hydrochloric acid solution. The combined aqueous layers were extracted with dichloromethane. The combined organic extracts were washed with two portions of 1 M aqueous sodium hydroxide solution. The combined basic aqueous layers were extracted with dichloromethane. The combined organic extracts were dried with sodium sulfate and concentrated. Column chromatography afforded 475 mg (84%) of the title compound as a light yellow amorphous mass.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:33]=[CH:32][CH:31]=[CH:30][C:7]=1[O:8][CH2:9][CH:10]([OH:29])[CH2:11][N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][C@H:13]1[C:25]([O:27]C)=[O:26])(=[O:4])[CH3:3].O.[OH-].[Li+].[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(#N)C.O>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[C:2]([NH:5][C:6]1[CH:33]=[CH:32][CH:31]=[CH:30][C:7]=1[O:8][CH2:9][CH:10]([OH:29])[CH2:11][N:12]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][C@H:13]1[C:25]([OH:27])=[O:26])(=[O:4])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@H](Oc2ccc(Cl)cc2)CN1CC(O)COc1ccccc1NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)Nc1ccccc1OCC(O)CN1C[C@@H](Oc2ccc(Cl)cc2)C[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
Compound (i) (50 mg, 0.1 mmol) was dissolved in acetonitrile (2 ml) and water (3 ml). Lithium hydroxide hydrate (8 mg, 0.2 mmol) dissolved in water (0.5 ml) was added. The reaction was complete after 0.5 h as determined by analytical HPLC. The mixture was acidified with TFA and purified by preparative RP-HPLC using acetonitrile and water containing 0.1% TFA as mobile phase. The appropriate fraction was concentrated in vacuo and the residue lyophilized from acetic acid to give the title compound as a white amorphous solid (27 mg, 48%). The substance is a diastereomeric mixture.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1.[CH2:23]([NH2:25])[CH3:24]>C(O)C.C1COCC1>[CH2:23]([NH:25][CH2:2][CH2:3][CH2:4][C:5]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][O:6]1)[CH3:24]
Reactant: CCN
Reactant: N#Cc1ccc2c(c1)COC2(CCCI)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCNCCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Yield: 56.7 %

Procedure:
To a stirred solution of 1-(3-iodopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (12.9 g, 30 mmol, 8% pure) in ethanol (150 mL) was added a solution of ethylamine (20.3 g, 450 mmol) in THF (50 mL) portionwise, and the mixture was stirred over night. The solution was evaporated, and was dissolved/suspended in water. The pH was adjusted to 12 using aqueous sodium hydroxide solution (2M) and was extracted with ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. This oil was purified by silica chromatography using 50% v/v ethyl acetate/heptane as eluent, followed by 10% v/v triethylamine/40% v/v ethyl acetate/heptane followed by 20% v/v triethylamine/ethyl acetate to give the title compound (5.52 g, 57%) as a pale yellow oil. 1H NMR (CDCl3) δ 1.05 (t, 3H), 1.2-1.6 (m, 2H), 2.15 (ddd, 1H), 2.24 (ddd, 1H), 2.57 (q, 2H) 2.58 (t, 2H), 5.12 (dt, 1H), 5.20 (dt, 1H), 7.00 (t, 2H), 7.38 (d, 1H), 7.42 (dd, 2H), 7.49 (s, 1H), 7.58 (ddt, 1H).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5]CC[CH2:2]1.C1(C)C=CC(S(O)(=O)=[O:14])=CC=1.[C:18]1([CH3:24])C=CC=CC=1>>[C:18]([O:6][CH2:1][CH3:5])(=[O:14])[CH3:24].[CH2:1]([OH:6])[CH3:2]
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCCC1
Product: CCO
Product: CCOC(C)=O
Temperature: 55 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
2-Amino-4,5-dimethoxyacetophanone oxime (1.0 g, 4.76 mmol) was suspended in 35 ml toluene, and cyclopentanone (0.42 ml, 4.76 mmol) was added, followed by 10 mg of p- toluenesulfonic acid. The mixture was stirred at 55° C. for 24 hours. The resultant solid was collected by filtration and recrystallized from ethyl acetate-ethanol (39% yield). m.p. 225°-227 C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[N+:13]([O-])=O)[CH3:2]>[Pd].CO>[NH2:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C(=O)OC)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Charged methyl 4-ethyl-3-nitrobenzoate (5.0 g, 23.92 mmol), Pd/C (500 mg) and methanol (50 mL) to a flask, purged with hydrogen and stirred at r.t. overnight. It was then filtered and concentrated to give 4.0 g of the title compound (94%). 1H NMR (400 MHz, CDCl3): δ 1.26 (3H, t, J=7.6 Hz), 2.54 (2H, q, J=7.6 Hz), 3.73 (2H, s), 3.87 (3H, s), 7.12 (1H, d, J=8.0 Hz), 7.35 (1H, s), 7.41 (1H, d, J=7.6 Hz). [M+H] Calc'd for C10H13NO2, 180; Found, 180.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: BrP(Br)Br
Reactant: OCC1CCc2ccccc2C1
Solvent: ClCCl
Product: BrCC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 124.9 %

Procedure:
A solution of 2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene (2.28 g, 14.0 mmol) in 100 ml of CH2Cl2 was treated with PBr3 (1.28 g, 4.73 mmol) at 0° C. The mixture was stirred at room temperature for 72 hours then poured onto 100 g of ice. The organic layer was isolated, washed with 10% K2CO4 aqueous solution, H2O , sat'd brine, and then dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, EtOAc:hexane, 1:10) to give a colorless oil (1.33 g, 41.6%); 1H NMR (CDCl3, 300 MHz) δ 1.55 (m, 1H), 2.11 (m, 1H), 2.11 (m, 2H), 2.58 (dd, J1 =16.2 Hz, J2 =10.2 Hz, 1H), 2.80-3.10 (m, 3H), 3.45 (d, J=6.3 Hz, 2H), 7.10 (m, 4H).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:12]([OH:14])=O)[CH3:7])[CH3:2].[NH2:21][C@@H:22]([CH2:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[CH:38]=1)[C@H:23]([OH:35])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH3:34])[CH:28]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.C(Cl)C[Cl:66]>C(Cl)Cl>[ClH:66].[ClH:66].[ClH:66].[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:12]([NH:21][C@@H:22]([CH2:36][C:37]1[CH:38]=[C:39]([F:44])[CH:40]=[C:41]([F:43])[CH:42]=1)[C@H:23]([OH:35])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH3:34])[CH:28]=1)=[O:14])[CH3:7])[CH3:20]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCN(CC)CCN(C)Cc1cc(C)cc(C(=O)O)c1
Reactant: ClCCCl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(CN(C)CCN(CC)CC)c2)c1
Product: Cl
Reaction time: 8 h

Procedure:
To a stirred solution of 3-{[[2-(diethylamino)ethyl](methyl)amino]methyl}-5-methylbenzoic acid (267 mg, 0.959 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol prepared by the method of EXAMPLE SP-272 (391 mg, 0.959 mmol), HOBt (129 mg, 0.959 mmol), and N,N-diisopropylethylamine (496 mg, 3.84 mmol) in methylene chloride (5 mL) is added EDC (331 mg, 1.73 mmol). The reaction mixture is stirred overnight and then partitioned between ethyl acetate and water. The organic layer is washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 9:1:1 methylene chloride/methanol/ammonium hydroxide) gives the title compound. ESI MS m/z 595.4 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1)=[O:2].[OH:11]O>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1)([OH:11])=[O:2]
Reactant: O=Cc1ccc(CO)cn1
Reactant: OO
Solvent: O
Product: O=C(O)c1ccc(CO)cn1
Yield: 97 %

Procedure:
2-Formyl-5-hydroxymethylpyridine (5.7 g, 0.042 mol) was dissolved in 40 mL of H2O and treated with 10 mL of aqueous 30% H2O2 at room temperature for 16 h. The mixture was concentrated to about 20 mL and cooled, and the precipitated acid was collected by filtration. 2-Carboxy-5-hydroxymethylpyridine was obtained in 97% yield (6.1 g). A portion was recrystallized from H2O to obtain an analytical sample. These white crystals sublimed at about 220° C., IR (mull) 3200, 1670, 1600, 1380, 1070, 870, 850, 800 cm-1 ; 1H NMR (Me2SO-d6) δ4.73 (s, 2, CH2OH), 7.9-8.2 (m, 2, 3', 4'--H), 8.67 (m, 1, 6'--H); MS calcd for C7H7NO3 153.0426, found 153.0429.
Reaction SMILES: [CH2:1]([O:5][Zr:6](OCCCC)([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].C(CC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:13]([O:12][Zr:6]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCO[Zr](OCCCC)(OCCCC)OCCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CCCCO[Zr](OCCCC)OCCCC

Procedure:
In 88 g of toluene was dissolved 38.3 g (0.1M) of tetra-n-butoxyzirconium, and 10.0 g (0.1M) of acetylacetone was gradually added to the resulting solution with stirring. An exothermic reaction of the mixture took place to give tri-n-butoxyzirconium acetylacetonato.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([S:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([F:42])[F:41])=[C:9]([S:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Sc3ccc(Cl)cc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of [8-chloro-3-(4-chlorophenylsulfanyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.26 g), N,N-dimethylformamide (5.0 mL), potassium carbonate (0.25 g) and acetic acid chlorodifluoromethyl ester (0.13 mL) was stirred at 80° C. for 17 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and cyclohexane (7:3 by volume) to afford title compound, 0.044 g.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:36])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]([CH3:36])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:22]1)=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-{(S)-3-[2-((S)-2-tert-butoxycarbonylaminopropionylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (2.054 g, 4.04 mmol) in DCM (40 mL) was added TFA (14 mL) and the mixture stirred at RT for 1.5 h. Toluene was added and the volatiles removed in vacuo. The resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording the title compound as a purple oil (1.443 g, 87%). LCMS (Method B): RT 1.60 min [M+H]+ 409.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[S:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:24](=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]#N>O>[F:1][C:2]1[C:3]([NH:17][C:18](=[N:20][CH2:21][CH2:22][CH3:23])[S:19][CH2:24][CH2:31][CH3:30])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: CCCNC(=S)Nc1nc(OCc2ccc(C)cc2)ncc1F
Reactant: O=C([O-])[O-]
Reactant: CC#N
Agent: [K+]
Solvent: O
Product: CCCN=C(Nc1nc(OCc2ccc(C)cc2)ncc1F)SCCC
Reaction time: 0.33 h
Yield: 63 %

Procedure:
To a magnetically stirred solution of 1-[5-fluoro-2-(4-methyl-benzyloxy)-pyrimidin-4-yl]-3-propyl-thiourea (0.50 g, 1.40 mmol) in CH3CN (4 mL), was added potassium carbonate (0.20 g, 1.40 mmol) at room temperature and the mixture was stirred for 20 min. N-propylbromide (0.19 g, 1.40 mmol) was added at room temperature and the resulting mixture stirred for 15 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent evaporated. The crude mixture was purified on silica (EtOAc/hexanes gradient) and evaporation of the product fractions gave 0.335 g (63%) of 1-[5-fluoro-2-(4-methyl-benzyloxy)-pyrimidin-4-yl]-2,3-dipropyl-isothiourea as a pale yellow viscous liquid: 1H NMR (300 MHz, CDCl3) δ 10.56 (bs, 1H), 8.09 (d, J=2.6 Hz, 1H), 7.31 (m, 2H), 7.24 (m, 2H), 5.28 (s, 2H), 3.28 (dd, J=13.6, 6.5 Hz, 4H), 2.36 (s, 3H), 1.62 (m, 4H), 1.0 (t, J=7.4 Hz, 4H); HPLC-MS (ESI) m/z 377 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C@@:13]3([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[C:9]([CH3:27])([CH3:26])[O:8][C:5]2=[CH:6][CH:7]=1.[F:28][CH:29]([F:39])[C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[F:39][CH:29]([F:28])[C:30]1[N:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[C:4]3[C@@:13]4([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[N:14]4)[C:10]4([CH2:11][CH2:12]4)[C:9]([CH3:27])([CH3:26])[O:8][C:5]3=[CH:6][CH:7]=2)=[O:37])=[N:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21CC1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3cnc(C(F)F)cn3)ccc1OC(C)(C)C21CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To an ice-water cooled mixture of tert-butyl [(4′R)-6′-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (430 mg, 1.15 mmol), 5-(difluoromethyl)pyrazine-2-carboxylic acid (221 mg, 1.27 mmol) and 1H-benzotriazol-1-ol (170 mg, 1.26 mmol) in chloroform (8.6 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (244 mg, 1.28 mmol). The mixture was stirred at room temperature overnight and directly purified by silica gel column chromatography (precolumn: basic silica gel, main column: neutral silica gel, hexane/ethyl acetate=2:1-1:1-0:100) to afford tert-butyl [(4′R)-6′-({[5-(difluoromethyl)pyrazin-2-yl]carbonyl}amino)-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (373 mg).
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[Li]>>[CH3:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH2:20][CH2:19][C:17]1[O:18][C:14]2[CH:13]=[CH:12][C:11]([C:7]3[CH:6]=[C:5]([C:4]([C:31]4[S:30][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH:10]=[CH:9][CH:8]=3)=[CH:27][C:15]=2[CH:16]=1
Reactant: [Li]c1cccs1
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(=O)c4cccs4)c3)ccc2o1
Yield: 53 %

Procedure:
The product from Example 145 and 2-thienyllithium were processed as described in Example 146 to provide the title compound (53% yield). MS (ESI APCI) m/z 416 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.18 (d, 3 H), 1.38-1.53 (m, 1 H), 1.73-1.86 (m, 2 H), 1.95-2.08 (m, 1 H), 2.24-2.36 (m, 1 H), 2.42-2.61 (m, 2 H), 2.95-3.15 (m, 2 H), 3.19-3.34 (m, 2 H), 6.63 (d, 1 H), 7.27 (d, 1 H), 7.48-7.57 (m, 2 H), 7.63 (dd, 1 H), 7.76-7.84 (m, 3 H), 7.90-7.98 (m, 2 H), 8.07 (dd, 1 H).