Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[C:24]([NH2:29])[N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1>CCO.CCOC(C)=O.[Pd]>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH2:29])[N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nccc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of 170 mg (0.38 mMol) 5-(2-amino-6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 19 ml EtOH/EtOAc 1:1 in hydrogenated in the presence of 80 mg Pd/C (10%; Engelhard 4505). The catalyst is filtered off and the filtrate diluted with EtOAc and sat. Na2CO3/H2O 1:1. The aqueous layer is extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; EtOAc/hexane 3:2→EtOAc) gives the title compound: MS: [M+1]+=416; TLC(hexane/EtOAc 3:7): Rf=0.14; HPLC: AtRet=12.0.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30]1([CH:34]=O)[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:34][CH:30]4[CH2:33][CH2:32][CH2:31]4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=CC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
In 1,2-dichloroethane (7 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g) and cyclobutanecarboaldehyde (0.5 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 4 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclobutylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.47 g) as yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]1([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:6].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C(C)=CC=CC=1C.[I-].[Na+]>O>[C:16]1([NH:15][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]2([CH2:13][CH3:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC1(OC(=O)CCCCl)CCCC1
Reactant: Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCC1(OC(=O)CCCNc2ccccc2)CCCC1
Temperature: 80 °C
Reaction time: 36 h
Yield: 74.1 %

Procedure:
In a nitrogen atmosphere, a mixture of 15 g of 1-ethylcyclopentyl 4-chlorobutyrate, 19 g of aniline, 7.3 g of 2,6-lutidine, and 1.5 g of sodium iodide was heated at 80° C. and stirred for 36 hours at the temperature. The reaction mixture was cooled, after which 15 g of water was added dropwise to quench the reaction. This was followed by ordinary aqueous work-up and vacuum distillation (135° C./13 Pa), recovering 14 g (yield 76%) of 1-ethylcyclopentyl 4-(phenylamino)butyrate.
Reaction SMILES: [F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]2[C:23]=1[CH:24]=[N:25][C:26]([CH3:33])=[N:27]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:19][CH3:20])=[C:4]([C@H:8]([CH3:18])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:21][C:22]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]3[C:23]=2[CH:24]=[N:25][C:26]([CH3:33])=[N:27]3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=O)C(F)(F)F
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Agent: [Ti+4]
Agent: CC[O-]
Product: COc1c(F)cccc1[C@H](C)C[C@@](O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F

Procedure:
In the same way as in Example 1, 250 mg (0.85 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal, 185 mg (1.05 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.4 ml of titanium tetraethoxide are reacted to give (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)pentan-2-ol. 430 mg of resultant crude imine are cyclized in the same way as in Example 1 at −30° C. using 8 ml (8 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-75%) yields 67 mg of product.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.C(OCC)(=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][N:55]([C:58](=[O:69])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:56][CH2:57]1)[CH2:49][NH:48][C:23]([C:20]1[CH:19]=[CH:18][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[F:10])=[CH:22][CH:21]=1)=[O:25]
Reactant: O=C(O)c1ccc(-c2ccccc2F)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
DIPEA (71 mg, 0.09 mL, 0.55 mmol) was added to a stirred solution of 2′-fluoro-biphenyl-4-carboxylic acid (40 mg, 0.18 mmol) in DMF (1 mL). HOBT (30 mg, 0.22 mmol) and EDCI (43 mg, 0.22 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (78 mg, 0.22 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and then extrated with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford 35 mg (36.8%) of 2′-fluoro-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 91.09%. 1H NMR (DMSO-d6): δ 8.02-7.94 (d, 2H), 7.9-7.72 (m, 2H), 7.72-7.64 (m, 3H), 7.64-7.54 (m, 2H), 7.54-7.42 (m, 1H), 7.4-7.3 (m, 2H), 4.2 (m, 2H), 3.8-3.4 (m, 2H), 3.2-3 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([CH:26]=[CH2:27])[CH:3]=1.C([O-])(=O)C.[Na+].O>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:24][CH:25]=1)[C:6](=[O:7])[N:8]([CH2:9][C:10]1[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=1)[CH:27]=[CH:26]2
Reactant: C=Cc1cc(Cl)ccc1C(=O)NCc1ccnc2cc(OC)c(OC)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Cn3ccc4cc(Cl)ccc4c3=O)c2cc1OC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-Chloro-N-((6,7-dimethoxyquinolin-4-yl)methyl)-2-vinylbenzamide (0.084 g, 0.22 mmol), sodium acetate (0.036 g, 0.44 mmol), and palladium acetate (0.002 g, 0.011 mmol) were combined in DMSO (5 ml). The reaction mixture was stirred under an oxygen balloon at 100° C. overnight. The mixture was poured into water and extracted with ethyl acetate three times. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by prep-TLC plate with ethyl acetate to give 6-chloro-2-((6,7-dimethoxyquinolin-4-yl)methyl)isoquinolin-1(2H)-one. MS (ESI, pos. ion) m/z: 381 (M+1). 1H NMR (CDCl3): 4.03 (6H, s), 4.80 (1H, d), 5.95 (1H, d), 5.40 (2H, s), 7.05 (1H, d), 7.40 (1H, s), 7.56 (2H, m), 7.70 (1H, s), 7.87 (1H, d), 8.64 (1H, d).
Reaction SMILES: [Cl-].[Li+].[C:3]([Li])([CH3:6])([CH3:5])[CH3:4].FC(F)(F)S(O[C:14]1[C:15]2[CH:16]=[C:17]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:18]=[CH:19][C:20]=2[C:21]([CH3:25])([CH3:24])[CH2:22][CH:23]=1)(=O)=O>C1COCC1>[CH3:4][C:3]1([CH3:6])[C:14]2[CH:23]=[CH:18][C:17]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)=[CH:16][C:15]=2[C:20]([C:21]([CH3:22])([CH3:24])[CH3:25])=[CH:19][CH2:5]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: [Li]C(C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C(C)(C)C)=CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 35.1 mg (0.39 mmol) of cuprous cyanide and 16.6 mg (0.39 mmol) of lithium chloride was flame dried under vacuum, cooled to room temperature and dissolved in 1.5 ml of THF. This solution was cooled to -78° C. and 50.2 mg (0.46 mL, 0.784 mmol) of tert-butyllithium (1.7M solution in pentane) was added forming a clear yellow solution. The reaction mixture was stirred at -78° C. for 15 minutes and then 125.0 mg (0.26 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66) was added as a solution in 0.5 ml of THF. After 10 minutes the reaction was quenched at -78° C. with 1.5 ml of a 2:1 (v/v) mixture of sat. aqueous NH4Cl and 5% NaOH. The mixture was extracted with EtOAc and the combined organic layers were washed with water and brine. The organic phase was dried over MgSO4, concentrated in vacuo and purified by column chromatography (silica, 5% EtOAc-hexanes) to give a clear yellow oil (7:5 ratio of title compounds). The two compounds were separated by HPLC (partisil 10, 2% EtOAc-hexanes) to give the title compounds as colorless oils.
Reaction SMILES: N.C([N:9]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]1=[O:23])C1C=CC=CC=1.CCO>C1COCC1>[NH:14]1[CH2:15][CH2:16][C:11]2([C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:9][C:10]2=[O:23])[CH2:12][CH2:13]1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2C12CCNCC2
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCNCC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
At −78° C., to liquid NH3 (20 ml) is added dropwise a solution of 1-benzylspiro[indole-3,4′-piperidin]-2(1H)-one (2 mmol) in THF (30 ml) and the mixture is stirred at −78° C. for 10 min. Li (42 mg, 6 mmol) is added in 3 portions and the resulting dark blue solution is stirred at −78° C. for 2 h. Anhydrous EtOH (1 ml) is added dropwise and the mixture is allowed to warm to rt overnight. Solvent is removed in vacuo and the resulting title compound (a light yellow solid) is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:7][NH:8]2)=[CH:4]C=1C#N.S(=O)(=O)(O)O.[C:27]([OH:30])(=[O:29])[CH3:28]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[N:7][NH:8]2)=[CH:4][C:28]=1[C:27]([OH:30])=[O:29]
Reactant: N#Cc1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc2c(/C=C/c3cccc(F)c3)n[nH]c2cc1F
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a suspension of 544 mg of 6-fluoro-3-[(E)-2-(3-fluorophenyl)-vinyl]-1H-indazole-5-carbonitrile obtained by Example 100 in 2 mL of acetic acid and 3 mL of water was added 6 mL of concentrated sulfuric acid, and stirred at 110° C. for 12 hours. After allowing to cool, the reaction solution was added with ice, and extracted with a mixed solvent of 200 mL of ethyl acetate and 50 mL of tetrahydrofuran. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 491 mg of the title compound as pale brown crystals.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:1][CH:2]([CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CN1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CN1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a mixture of benzyl 4-(2-hydroxypropyl)piperazine-1-carboxylate (from step 1, 1.7 g, 6.1 mmol) in DCM (20 mL) was added DIPEA (2.1 mL, 12 mmol) followed by methanesulfonyl chloride (0.70 mL, 9.0 mmol) at 0° C. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with saturated NaHCO3 solution and extracted with DCM. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to provide crude product (2.22 g) which was used in next step without further purification. LCMS calculated for C16H25N2O5S(M+H)+: m/z=357.1; Found: 357.3.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].[F:20][C:21]([F:38])([F:37])[C:22]([N:24]1[C:32]2[C:27](=[CH:28][C:29]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:23]>O>[C:1]1([C:7]2[NH:8][C:9](=[O:12])[N:10]([S:33]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[N:24]([C:22](=[O:23])[C:21]([F:38])([F:20])[F:37])[CH2:25][CH2:26]4)(=[O:34])=[O:35])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: O=c1[nH]cc(-c2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21)C(F)(F)F
Temperature: 0 °C
Yield: 70 %

Procedure:
4-Phenyl-2,3-dihydro-1H-2-imidazolone (4 g, 24.84 mmol) prepared in Preparation 1 was suspended in 30 m of dimethylformamide and cooled down to 0° C. After sodium hydride (60% oily, 1.09 g, 27.3 mmol) was added thereto, the resulting mixture was stirred for a few minutes at 0° ° C. until it became a clear solution. To the reaction mixture was added portionwise at 0° C. the N-trifluoroacetyl-indoline-5-sulfonylchloride (8.56 g, 27.32 mmol) prepared in Preparation 2. The reaction mixture was stirred at room temperature for 4 hours, cooled down again to 0° C., and then water was slowly added to the mixture until precipitate was formed. The resulting precipitate was collected, washed with water, and dried to afford 7.6 g of 4-phenyl-1-(N-trifluoroacetylindoline-5-sulfonyl)-2-imidazolone.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:5]([Cl:24])=[C:6]([C:20]([Cl:23])=[CH:21][CH:22]=1)[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([Br:19])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1.CS(Cl)(=O)=O>N1C=CC=CC=1.C(N(CC)C=O)C>[Br:19][C:15]1[N:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:6]3[C:20]([Cl:23])=[CH:21][CH:22]=[C:4]([N:3]=[CH:15][N:11]([CH2:12][CH3:13])[CH2:10][CH3:9])[C:5]=3[Cl:24])[C:10]2=[N:17][C:16]=1[CH3:18]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N)c3Cl)cccn2c1Br
Agent: CCN(C=O)CC
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCN(C=Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl)CC
Temperature: 0 °C
Yield: 127.3 %

Procedure:
To a suspension of 8-(3-amino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine dihydrochloride (100 mg) in a mixture of pyridine (0.5 ml) and N,N-diethylformamide (1.5 ml) was added methanesulfonyl chloride (27 mg) in one portion. The mixture was stirred at 60°-70° C. for one and half hours, cooled, and poured into ice water. The separated oil was extracted with dichloromethane. The extract was washed with water, dried, and concentrated in vacuo to give a brown oil, which was purified by preparative thin-layer chromatography on silica gel (5% solution of methanol in dichloromethane) to give 3-bromo-8-[2,6-dichloro-3-[(N,N-diethylaminomethylene)amino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (65 mg) as crystals.
Reaction SMILES: [CH3:1][N:2]1[C:20](=[O:21])[N:5]2[C:6]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:7]=3[O:8][CH2:9][C:10]3([CH2:12][O:11]3)[C:4]2=[N:3]1>CO.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10]([OH:11])([CH3:12])[C:4]3[N:5]([C:20](=[O:21])[N:2]([CH3:1])[N:3]=3)[C:6]=2[CH:16]=1
Reactant: Cn1nc2n(c1=O)-c1cc([N+](=O)[O-])ccc1OCC21CO1
Agent: [Pd]
Solvent: CO
Product: Cn1nc2n(c1=O)-c1cc(N)ccc1OCC2(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
2-Methyl-9-nitro-5H-spiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazepine-4,2′-oxiran]-1(2H)-one (250 mg) and 10% Pd—C were suspended in methanol (10 mL). The reaction mixture was shaken at room temperature under H2 atmosphere (30 psi) for one hour. The catalyst was filtered off over celite and washed with methanol (5×50 mL). The filtrate was evaporated to give 9-amino-4-hydroxy-2,4-dimethyl-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d][1,4]oxazepin-1(2H)-one (200 mg). m/z=263.12 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:20][S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])([CH:17]([F:19])[F:18])[CH2:9][C:10](OC(C)(C)C)=[O:11])[C:5]([F:27])=[CH:4][CH:3]=1.BrC1N=C([C@](N[S@@](C(C)(C)C)=O)(C(F)F)CC(OC(C)(C)C)=O)C(F)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].BrC1N=C([C@](N[S@@](C(C)(C)C)=O)(CCO)C(F)F)C(F)=CC=1>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:20][S@@:21]([C:23]([CH3:25])([CH3:24])[CH3:26])=[O:22])([CH2:9][CH2:10][OH:11])[CH:17]([F:19])[F:18])[C:5]([F:27])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[C@@](N[S@](=O)C(C)(C)C)(c1nc(Br)ccc1F)C(F)F
Agent: CC(C)(C)OC(=O)C[C@](N[S@](=O)C(C)(C)C)(c1nc(Br)ccc1F)C(F)F
Agent: CC(C)(C)[S@@](=O)N[C@](CCO)(c1nc(Br)ccc1F)C(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](CCO)(c1nc(Br)ccc1F)C(F)F
Temperature: -10 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
To a 100-mL round-bottomed flask were added a mixture of (R)-tert-butyl 3-(6-bromo-3-fluoropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate and (5)-tert-butyl 3-(6-bromo-3-fluoropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4,4-difluorobutanoate (0.33 g, 0.697 mmol) and DCM (6.97 ml). The solution was cooled to −10° C. and lithium aluminum hydride, 1.0m solution in THF (1.394 ml, 1.394 mmol) was added dropwise over 10 min. The reaction mixture was stirred −10° C. for 4 h. Sodium sulfate decahydrate (1.8 g, 5.6 mmol) was added and the mixture was stirred for 10 min. The solid was filtered and washed with EtOAc. The filtrate was concentrated in vacuo. Purification by silica gel chromatography (0-70% EtOAc/hexane) afforded a 3:1 mixture of (R)-N-((R)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1-difluoro-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide and (R)-N-((S)-2-(6-bromo-3-fluoropyridin-2-yl)-1,1-difluoro-4-hydroxybutan-2-yl)-2-methylpropane-2-sulfinamide (0.176 g, 0.436 mmol, 62.6% yield) as a colorless oil. MS m/z=403, 405 M+ Calculated for C13H18BrF3N2O2S: 403.26. Used directly in the following step.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:28]2[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:33])=[C:26]([F:32])[CH:27]=2)=[CH:8][C:7]=1[CH2:14][N:15]([CH:17]1[CH2:19][CH2:18]1)[CH3:16])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1ccc(C(=O)OC(C)C)c(CN(C)C2CC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1F

Procedure:
Following General Procedure B and using 2-[(cyclopropyl-methyl-amino)methyl]-4-ethynyl-benzoic acid isopropyl ester (Intermediate 122, 0.05 g, 0.18 mmol), 2-fluoro-4-iodo phenylacetic acid methyl ester (0.07 g, 0.24 mmol), triethyl amine (2 mL), copper(I)iodide (0.04 g, 0.21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 15-16% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.04 g, 50%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[K+]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10]
Reactant: N#CCc1ccccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Product: NCCc1ccccc1Br
Yield: 92.9 %

Procedure:
10.0 g (51.0 mmol) 2-bromophenylacetonitrile were dissolved in 80 ml ether and the solution was added dropwise to 5.81 g (153 mol) lithium aluminium hydride in 230 ml ether. The mixture was heated under reflux for three hours, while stirring, and, after cooling, 80 ml potassium hydroxide solution (10 wt. %) were slowly added dropwise, with vigorous stirring. After stirring overnight, the supernatant was decanted off, the residue was rinsed twice with 100 ml ether each time, the combined organic phases were dried over anhydrous magnesium sulfate and filtered and the filtrate was concentrated on a rotary evaporator (500-10 mbar). 9.48 g 2-(2-bromo-phenyl)-ethylamine (93% of theory) were obtained in this manner.
Reaction SMILES: [F:1][C:2]1([F:37])[CH2:5][CH:4]([CH:6]([NH:21][C:22]2[CH:23]=[N:24][C:25]([N:28]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:30]=[CH:29]3)=[CH:26][CH:27]=2)[C:7]2[CH:20]=[CH:19][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O.O1CCCC1.O.[OH-].[Li+]>CO>[F:37][C:2]1([F:1])[CH2:5][CH:4]([CH:6]([NH:21][C:22]2[CH:23]=[N:24][C:25]([N:28]3[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:30]=[CH:29]3)=[CH:26][CH:27]=2)[C:7]2[CH:20]=[CH:19][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: O=C([O-])CCNC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(C(Nc2ccc(-n3cnc(C(F)(F)F)c3)nc2)C2CC(F)(F)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To a flask containing 3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoate (7.00 mg, 0.0100 mmol) was added water (0.0650 mL), tetrahydrofuran (0.0650 mL), and methanol (0.0650 mL). Lithium hydroxide monohydrate (27.3 mg, 0.650 mmol) was then added. The suspension was stirred at room temperature for 2 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give (+/−)-3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol-1-yl)pyridin-3-ylamino)methyl)benzamido)propanoic acid (4.5 mg, 70%) of a glass-like material. 1H NMR (400 MHz, CDCl3) δ 8.36-8.34 (m, 1H), 8.16-8.12 (m, 1H), 7.86 (d, J=2.9 Hz, 1H), 7.84-7.77 (m, 2H), 7.58-7.51 (m, 2H), 7.39 (dd, J=8.8, 0.6 Hz, 1H), 7.10 (dd, J=8.8, 2.9 Hz, 1H), 4.48 (d, J=8.8 Hz, 1H), 3.63 (t, J=6.9 Hz, 2H), 2.94-2.73 (m, 1H), 2.64 (t, J=6.9 Hz, 2H), 2.61-2.49 (m, 2H), 2.49-2.33 (m, 2H). MS (M+1): 524.3.