Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:35])([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:36].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[N:49]1([CH2:55][CH2:56]O)[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>ClCCl>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[CH:21]=[N:22][C:23]([N:26]4[CH2:31][CH2:30][C:29]([CH3:35])([C:32]([O:34][CH2:56][CH2:55][N:49]5[CH2:54][CH2:53][O:52][CH2:51][CH2:50]5)=[O:33])[CH2:28][CH2:27]4)=[N:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][C:12]=1[CH3:36]
Reactant: Cc1nc2ccc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Reactant: OCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2ccc(-c3cnc(N4CCC(C)(C(=O)OCCN5CCOCC5)CC4)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
The sodium salt of Example 44 (200 mg, 0.378 mmol) was suspended in dichloromethane (25 mL). A drop of DMF was added, followed by oxalyl chloride (50 mg, 0.39 mmol). The mixture was stirred at room temperature for 2 h, then 2-(morpholin-4-yl)ethanol (99 mg, 0.75 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was washed with aqueous sodium bicarbonate solution and the organic layer was concentrated in vacuo. Chromatography (silica, 0 to 10% MeOH in DCM), followed by freeze-drying, gave the title compound (35 mg, 15%) as an off-white solid. δH (DMSO-d6) 8.64 (s, 2H), 8.37 (s, 1H), 7.55-7.43 (m, 2H), 7.31-7.10 (m, 4H), 7.04-7.01 (m, 1H), 4.35 (s, 2H), 4.34-4.28 (m, 2H), 4.25-4.21 (m, 2H), 3.52-3.48 (m, 4H), 3.36-3.25 (m, 2H), 2.60-2.54 (m, 2H), 2.42-2.38 (m, 4H), 2.32 (s, 3H), 2.10-2.04 (m, 2H), 1.45-1.35 (m, 2H), 1.19 (s, 3H). LCMS (pH10): MH+ (621.8), RT 2.01 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([CH3:28])[CH:26]=O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16].C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:26][CH:25]([CH3:28])[CH2:24][C:21]2[CH:20]=[CH:19][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(C=O)Cc1ccc(C(C)C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NCC(C)Cc1ccc(C(C)C)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylamine (0.300 g, 1.19 mmol) and 3-(4-isopropylphenyl)isobutyraldehyde (0.272 g, 1.43 mmol) were combined in toluene (3 mL) and stirred at 110° C. for 1 hour. After cooling to room temperature, toluene was removed under vacuum and the mixture was diluted with THF (4 mL). Sodium cyanoborohydride (0.188 g, 2.98 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was adsorbed onto silica gel and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:30][CH:29]=1.N1(O)C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:36](=[O:37])/[CH:35]=[CH:34]/[C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccncc1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(/C=C/c1ccncc1)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 65 %

Procedure:
To a solution of the [6-[(4-chlorophenylsulfonyl) (2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (41 mg, 0.10 mmol) obtained in Example 351, (E)-3-(pyridin-4-yl)acrylic acid (15 mg, 0.10 mmol), benzotriazol-1-ol (14 mg, 0.10 mmol), and N-methylmorpholine (0.011 ml, 0.10 mmol) in dichloromethane (1 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19 mg, 0.10 mmol) at 0° C. The resulting mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer thus obtained was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography and a fraction obtained from the elution portion with ethyl acetate was concentrated under reduced pressure. The solid thus obtained was washed with diethyl ether and then collected by filtration, whereby the title compound (35 mg, 0.065 mmol, 65%) was obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:14])([F:13])[C:10]1=[O:15].[Cl-].[S:17](=[CH2:20])(=[O:19])=[O:18]>N1C(C)=CC=CC=1C.CCOCC>[CH3:20][S:17]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:12][C:11]([F:13])([F:14])[C:10]1=[O:15])(=[O:19])=[O:18]
Reactant: C=S(=O)=O
Reactant: O=C1N(c2ccccc2CO)CC1(F)F
Agent: [Cl-]
Solvent: Cc1cccc(C)n1
Solvent: CCOCC
Product: CS(=O)(=O)OCc1ccccc1N1CC(F)(F)C1=O
Temperature: 7 °C
Reaction time: 1.5 h

Procedure:
0.17 mmole of compound 4a is dissolved in 0.8 ml of 2,6-lutidine at 0° C., followed by the addition of 0.18 mmole of sulphonyl methane chloride to said solution. After stirring the reaction mixture for 90 min. at a temperature of 4 to 10° C., the solution is taken up in 1 ml of ether and then washed twice with 0.5 ml of saturated aqueous NaCl solution.
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].Cl.[OH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:3][Si:2]([CH3:5])([CH3:4])[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1
Reactant: C[Si](C)(C)Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 1.85 ml of chlorotrimethylsilane in 10 ml of CH2Cl2 is added dropwise to a solution of 2.0 g of trans-4-hydroxycyclohexylamine hydrochloride and 4.05 ml of triethylamine in 20 ml of CH2Cl2, cooled to 0° C. After stirring for 16 hours at room temperature, the mixture is hydrolyzed with water and extracted. The organic phase is washed successively with water, a 5% solution of Na2CO3 and saturated NaCl. After drying over MgSO4 and evaporation of the solvents, 1.43 g of amine (colorless liquid) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:29])=[C:10]([C:17]([NH:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24]CC)=[O:23])=[O:18])[N:11]=[C:12]2[C:15]#[N:16])=[CH:7][CH:6]=1.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:29])=[C:10]([C:17]([NH:19][CH2:20][C:21]([CH3:28])([CH3:27])[C:22]([OH:24])=[O:23])=[O:18])[N:11]=[C:12]2[C:15]#[N:16])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3Cl)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3Cl)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-(7-(2-chlorophenoxy)-1-cyano-4-hydroxyisoquinoline-3-carboxamido)-2,2-dimethylpropanoate (30 mg, 0.06 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 19 mg. MS: (−) m/z 437.95 (M−1).
Reaction SMILES: O[C:2]1([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[Al]>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH:4]1[CH2:5][CH:6]=[C:2]([C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nccs2)C1
Agent: [Al]
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2nccs2)CNC1
Temperature: 25 °C

Procedure:
tert-Butyl 3-hydroxy-3-(1,3-thiazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 0.0037 mol) was dissolved in trifluoroacetic acid (10.0 mL, 0.130 mol) under N2 at rt. The reaction flask was wrapped with aluminum foil and the mixture was stirred under reflux for 3 h. After cooling to rt the reaction mixture was concentrated in vacuo and used directly for the next step without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[F:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH2:59][CH2:60][O:61][CH3:62])(=[O:58])=[O:57])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH2:59][CH2:60][O:61][CH3:62])(=[O:57])=[O:58])[CH:43]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COCCS(=O)(=O)Nc1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COCCS(=O)(=O)Nc1cc(F)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 69 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (53 mg, 0.09 mmol) was treated with N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methoxyethanesulfonamide (80 mg, 0.22 mmol), sodium carbonate (24 mg, 0.22 mmol) and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (22 mg, 0.03 mmol) in 1,2-dimethoxyethane (2 ml) and water (0.5 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 70% n-hexane-ethyl acetate) to obtain 59 mg (69% yield, 78% purity) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:8][CH:7]=[C:6]([OH:9])[C:4](=[O:5])[CH:3]=1.C(N(CC)CC)C.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>C1COCC1>[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([O:9][C:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:8][CH:7]=1)=[O:23]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1cc(=O)c(O)co1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(=O)c(OC(=O)c2ccco2)co1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
Allomaltol (1.256 g, 10 mmol) was dissolved in 40 mL of anhydrous THF. The mixture was cooled to 0° C. Triethylamine (1.8 mL, 13 mmol) was added. Furan-2-carbonyl chloride (1.500 g, 11 mmol) was added dropwise. Cold bath was removed and the mixture was stirred at room temperature overnight. The reaction was extracted with EtOAc. The organic phase was washed with brine 2 times then dried over Na2SO4 and concentrated. The crude product was purified with flash chromatography using EtOAc/hexanes to give the desired product as a brown solid (1.539 g, 70%). MP (136° C.). 1H NMR (CDCl3) δ (ppm): 2.30 (s, 3H), 6.29 (s, 1H), 6.55 (m, 1H), 7.37 (m, 1H), 7.64 (m, 1H), 7.94, (s, 1H). 13C NMR (CDCl3) δ (ppm): 19.8, 112.6, 115.4, 120.8, 140.5, 143.0, 147.9, 148.4, 155.4, 166.5, 172.1.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[CH:28]([O:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([CH3:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[C:7](=[O:8])[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=2[CH3:27])=[CH:34][CH:33]=1)([CH3:30])[CH3:29]
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCc1nc(C)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 89.3 %

Procedure:
To a solution of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g) and 4-isopropoxyphenylboronic acid (0.64 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.01 g, 89%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:39]([O:46][C:47](=[O:51])[C@@H:48](O)[CH3:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][C@@H:48]([C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:51])[CH3:49])[C:33]3[C:28](=[CH:29][C:30]([CH3:37])=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester and 341 mg of (S)-2-Hydroxy-propionic acid benzyl ester in 15 ml of THF, 744 mg of Triphenyl-phosphane and 494 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.0 g.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].COC(=O)[O-].[CH3:21][NH+:22]1[CH2:26][CH:25]([CH3:27])[N:24]([CH3:28])[CH:23]1[CH3:29]>>[CH3:21][NH+:22]1[CH2:26][CH:25]([CH3:27])[N:24]([CH3:28])[CH:23]1[CH3:29].[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([O-:9])=[O:8])[C:5]=1[C:13]([O-:15])=[O:14])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Agent: CC1C[NH+](C)C(C)N1C
Agent: COC(=O)[O-]
Product: O=C([O-])c1cccc([N+](=O)[O-])c1C(=O)[O-]

Procedure:
Next, 3-nitrophthalic acid (0.1 mol) was added into a 1,2,3,4-tetramethyl imidazolinium methyl carbonate salt (0.1 mol) solution to induce a salt exchange reaction, thereby obtaining a 1,2,3,4-tetramethyl imidazolinium•3-nitrophthalate solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH2:26][OH:27])[N:9]=2)=[CH:4][CH:3]=1.CC1(C)N([O])C(C)(C)CC(OC)C1.[Br-].[K+].Cl[O-].[Na+]>C(Cl)Cl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@@:10]3([CH2:25][C@H:24]3[CH:26]=[O:27])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1CO)c1nnc(C)n1-2
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: COC1CC(C)(C)N([O])C(C)(C)C1
Agent: [Br-]
Solvent: ClCCl
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@]1(C[C@H]1C=O)c1nnc(C)n1-2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of ((1S,2R)-4′-(4-chlorophenyl)-2′,3′,9′-trimethylspiro[cyclopropane-1,6′-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine]-2-yl)methanol (300 mg, 0.752 mmol) in DCM (5 mL), a solution of 4-methoxy TEMPO (0.0135M in DCM) (1 mL, 0.0135 mmol), a solution of Aliquat 336 (0.074M in DCM) (0.5 mL, 0.037 mmol) and a solution of potassium bromide (0.25M in water) (0.3 mL, 0.075 mmol) were mixed and cooled to 0° C. before a solution of sodium hypochlorite (0.35M in water; buffered with NaHCO3 to pH˜8.6) was slowly added. After 30 min of vigorous stirring at 0° C., the aqueous layer was extracted with DCM. 2-Methyl-2-butene (0.5 mL) was added to the organic layer, before it was concentrated to dryness. The residue was used in the next step without purification. LRMS (M+H)+: 397 m/z.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[C:4]([C:9]([CH3:21])=[C:10]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>O1CCCC1.CO>[Br:1][C:2]1[C:3]([F:22])=[C:4]([C:9]([CH3:21])=[C:10]([N:12]([CH2:19][CH3:20])[CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCN(c1cc(Br)c(F)c(C(=O)OC)c1C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1cc(Br)c(F)c(C(=O)O)c1C)C1CCOCC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 105.1 %

Procedure:
To a solution of methyl 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoate (519 mg, 1.39 mmol) in Tetrahydrofuran (13 ml) and MeOH (4 ml) was added 4M NaOH (13.87 ml). The reaction mixture was stirred at 50° C. in air for 72 hours. The reaction mixture was acidified to pH 2-3 with 6M HCl and extracted with DCM (5×15 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 526 mg (95%) of 3-bromo-5-[ethyl(oxan-4-yl)amino]-2-fluoro-6-methylbenzoic acid as a beige foam. LC-MS 88%, 1.77 min (3 minute LC-MS method), m/z=359.9/361.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.43-7.31 (m, 1H), 4.00 (d, J=11.3 Hz, 2H), 3.41-3.29 (m, 2H), 3.16-2.91 (m, 3H), 2.40 (s, 3H), 1.84-1.59 (m, 4H), 0.99-0.82 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.[CH:17]1(/[CH:20]=[CH:21]/B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Cl:16][C:5]1[CH:4]=[CH:3][C:2](/[CH:21]=[CH:20]/[CH:17]2[CH2:19][CH2:18]2)=[CH:7][C:6]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1(C)OB(/C=C/C2CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(/C=C/C2CC2)ccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 5-bromo-2-chlorophenylcarbamate (from the previous step) (1.0 eq.) and (E)-2-(2-cyclopropylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (commercially available) (1.0 eq.) in toluene (0.2 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and water. The two phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% EtOAc/Hexanes to give (E)-tert-butyl 2-chloro-5-(2-cyclopropylvinyl)phenylcarbamate as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:39][CH:40]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2cncc(Br)c2)cc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5ccc(C(F)(F)F)cc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(4-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[C:12](=[O:25])[CH2:11][N:10]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:38]1C=CC=CC=1.CNC1C=CC=CC=1>>[CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][C:16]([N:18]([CH3:38])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[C:12](=[O:25])[CH2:11][N:10]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:9]1=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1ccccc1
Reactant: Nc1ccccc1
Solvent: CNc1ccccc1
Product: CN(C(=O)CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)c1ccccc1

Procedure:
Instead of the starting material compound of Example 270, that is, aniline, N-methylaniline was used for the similar procedure as in Example 270 to obtain the title compound.