Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([OH:24])=[O:23])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([O:24][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:23])[CH2:13][O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](COCc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 199.6 %

Procedure:
Into a solution of 25 g (0.076 mol) of N-(benzyloxycarbonyl)-O-benzylserine in 600 ml of CH2Cl2 cooled to −6° C. in an ice-salt bath was bubbled isobutylene, while 4.1 ml of concentrated sulfuric acid was added dropwise thereto. The mixture was stirred for 4 hours and worked up as described in Synthetic Commun., 26:2723 (1996) to give 29.24 g of product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([O:28]CC2C=CC=CC=2)=[C:16]2[C:21](=[O:22])[N:20]3[C@H:23]([CH3:26])[CH2:24][O:25][C@H:19]3[CH2:18][N:17]2[CH:27]=1)=[O:12]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:36])[C:15]([OH:28])=[C:16]2[C:21](=[O:22])[N:20]3[C@H:23]([CH3:26])[CH2:24][O:25][C@H:19]3[CH2:18][N:17]2[CH:27]=1)=[O:12]
Reactant: C[C@@H]1CO[C@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCc4ccccc4)c3C(=O)N12
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CO[C@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Yield: 85.7 %

Procedure:
To a solution of (3R,11aS)-N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (396 mg, 0.80 mmol) in methanol (30 mL) was added 10% Pd/C (25 mg). Hydrogen was bubbled through the reaction mixture via a balloon for 2 h. The resultant mixture was filtered through Celite with methanol and dichloromethane. The filtrate was concentrated in vacuo to give (3R,11aS)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl 5,7-dioxo-2,3,5,7,11,11a hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide as a pink tinted white solid (278 mg, 86%). 1H NMR (CDCl3) δ 11.47 (m, 1H), 10.29 (m, 1H), 8.82 (s, 1H), 7.36 (m, 1H), 6.82 (m, 2H), 5.81 (dd, J=0.6, 3.6 Hz, 1H), 4.65 (m, 2H), 4.47-4.38 (m, 3H), 3.93 (dd, J=12.0, 10.0 Hz, 1H), 3.75 (m, 1H), 1.49 (d, J=5.6 Hz, 3H); ES+ MS: 406 (M+1). The above material (278 mg, 0.66 mmol) was taken up in ethanol (10 mL) and treated with 1 N sodium hydroxide (aq) (0.66 mL, 0.66 mmol). The resulting suspension was stirred at room temperature for 30 min. Ether was added and the liquids were collected to provide the sodium salt of the title compound as a white powder (291 mg, 99%). 1H NMR (DMSO-d6) δ 10.68 (m, 1H), 7.90 (s, 1H), 7.85 (m, 1H), 7.20 (m, 1H), 7.01 (m, 1H), 5.20 (m, 1H), 4.58 (m, 1H), 4.49 (m, 2H), 4.22 (m, 2H), 3.74 (dd, J=11.2, 10.4 Hz, 1H), 3.58 (m, 1H), 1.25 (d, J=4.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[C:7]([CH2:12][C:13]#[CH:14])[CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH:16][C:17]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>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.[Cu](I)I.C(N(CC)CC)C>[OH:16][C:17]1[CH:26]=[C:25]([C:14]#[C:13][CH2:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[O:5][CH2:4][CH2:3][C:2]3([CH3:15])[CH3:1])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CCc1cccc2c1OCCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CCc2cccc3c2OCCC3(C)C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.18 g (5.9 mmol) of 3-(4,4-dimethylchroman-8-yl)-1-propyne, 1.60 g (5.9 mmol) of methyl 2-hydroxy-4-iodobenzoate and 60 ml of triethylamine are introduced into a three-necked flask under argon. The reaction mixture is degassed by sparging with nitrogen, 332 mg (0.46 mmol) of bis(triphenylphosphine)palladium(II) chloride and 134 mg of copper iodide are introduced and the mixture is stirred at room temperature for eight hours. The reaction mixture is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1N), and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica column eluted with heptane. After evaporating the solvents, an oil, which slowly crystallizes, is obtained and is recrystallized from heptane. 1.00 g (50%) of methyl 2-hydroxy-4-[3-(4,4-dimethylchroman-8-yl)prop-1-ynyl]benzoate is collected in the form of a white solid with a melting point of 92-93° C.
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:25])(=O)[CH2:2][CH3:3].Cl.[CH2:27]([O:30][NH2:31])[CH2:28][CH3:29].N1C=CC=CC=1.Cl>C(Cl)(Cl)Cl.O>[CH2:27]([O:30][NH:31][C:1](=[C:5]1[C:6](=[O:25])[CH2:7][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9][C:10]1=[O:11])[CH2:2][CH3:3])[CH2:28][CH3:29]
Reactant: CCC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: CCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCONC(CC)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reaction time: 5 h

Procedure:
0.2 Gram of 2-propionyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 10 ml of chloroform and 0.07 g of propoxyamine hydrochloride and 0.5 ml of pyridine were added to the resulting solution which was then stirred at 50°-60° C. for 5 hours. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. After removing chloroform, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.11 g of 2-(1-propoxyaminopropylidene)-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]#[CH:3].[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15]Br>>[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15][O:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:1][C:2]#[CH:3])=[CH:11][CH:10]=1
Reactant: C#CCOc1ccc(O)cc1
Reactant: CC(C)=CCBr
Product: C#CCOc1ccc(OCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 1, by reacting hydroquinone monopropargyl ether with 3-methyl-2-butenyl bromide, there is obtained 1-[(3-methyl-2-butenyl)oxy]-4-propargyloxy-benzene; B.P. 145°-148°C/1 mmHg.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1.[Cl:17][Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20].C(OCC)C>C1COCC1>[Cl:17][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH3:16])=[CH:9][CH:8]=1
Reactant: CC(C)[Si](Cl)(Cl)C(C)C
Reactant: COCOc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCOc1ccc([Si](Cl)(C(C)C)C(C)C)cc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 71.2 %

Procedure:
A solution of n-butyllithium (1.6M, 72.50 mL, 0.116 mol) was added slowly dropwise to a solution of bromo-4-methoxymethoxybenzene (25.23 g, 0.116 mol) in dry THF (110 mL) at −78° C. After stirring for 50 min at −78° C., dichlorodiisopropylsilane (21.00 mL, 0.116 mol) was charged into the flask. The reaction mixture was slowly allowed to warm to room temperature with stirring. Diethyl ether (100 mL) was added, the mixture was then stirred for 15 min and filtered. The filtrate was concentrated in vacuo to an oil. The oil was purified by short path distillation (116-128° C./0.18 mm Hg) to afford the compound (23.7 g, 71%) as a slightly cloudy pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9](=[N:13]O)[C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:17][N:16]=[C:10]([CH3:11])[C:9]=2[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CC(=O)C(=NO)C(=O)c1cccc(Cl)c1
Solvent: CCO
Product: Cc1n[nH]c(-c2cccc(Cl)c2)c1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.8 %

Procedure:
To a 0° C. solution of 1-(3-chlorophenyl)-2-(hydroxyimino)butane-1,3-dione (224.8 mg, 0.996 mmol) in 5 mL ethanol was dropwise added hydrazine (0.30 mL, 9.6 mmol). The reaction was warmed to room temperature and stirred for 15 hours. The crude reaction mixture was concentrated and purified by flash chromatography on silica gel (20 to 100% ethyl acetate in dichloromethane) to yield 113.3 mg (55%) of 5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-amine. LCMS (ESI) m+H=208.2; 1H NMR (400 MHz, DMSO-d6) δ: 12.20 (s, 1H), 7.94-7.57 (m, 2H), 7.40 (s, 1H), 7.27 (d, J=9.1, 1H), 2.12 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:22]([NH2:24])=[O:23])[N:12]3[C:17](S(C)=O)=[CH:16][C:15]([CH3:21])=[N:14][C:13]=23)=[C:4]([CH3:25])[CH:3]=1.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28].C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:22]([NH2:24])=[O:23])[N:12]3[C:17]([N:29]([CH2:30][CH2:31][CH3:32])[CH2:26][CH2:27][CH3:28])=[CH:16][C:15]([CH3:21])=[N:14][C:13]=23)=[C:4]([CH3:25])[CH:3]=1
Reactant: Cc1cc(S(C)=O)n2c(C(N)=O)cc(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CCCNCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)c1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C(N)=O)n12
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A mixture of 8-(4-bromo-2,6-dimethyl-phenyl)-4-methanesulfinyl-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carboxylic acid amide (100 mg), N,N-dipropylamine (48 mg) in ethanol (1 mL) was heated at reflux for 1 h. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=1:1) to give a solid. The solid was washed with a mixture of diisopropylether and ethyl acetate to give the title compound (50 mg).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([CH:69](OC)[O:70]C)[CH2:67][CH3:68])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C.ClCCl.FC(F)(F)C(O)=O.O>C1(C)C=CC=CC=1>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@@H:66]([CH2:67][CH3:68])[CH:69]=[O:70])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:52])([CH3:53])[CH3:54])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: CC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C)C(OC)OC
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
0.1 g (0.1 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)-propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxymethyl)propyl]-L-leucinamide was dissolved in3 ml of dichloromethane, 3 ml of trifluoroacetic acid and 90 mg of water and the mixture was stirred at room temperature for 30 minutes. The solution was diluted with 20 ml of toluene and the solvent was removed by evaporation. The resulting white solid was triturated with diethyl ether and filtered off. The solid was purified by RP-HPLC on a C18 Dynamax column (pore size 300 Å; column size 21.4 mm×50 mm). The elutiongradient comprised 90% SSA 10% SSB to 95% SSB 5% SSA over 8.5 minutes. After lyophilization overnight there were obtained 25 mg of 2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl]-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]butyraldehyde as a white foam. MS: m/e 819.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9]C)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH:17]([F:19])[F:18])[C:13]([CH3:20])=[N:12]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH:17]([F:19])[F:18])[C:13]([CH3:20])=[N:12]1
Reactant: COc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(Cl)c(-n2nc(C)n(C(F)F)c2=O)cc1O
Yield: 68.4 %

Procedure:
To a stirred solution of 16.0 g (0.053 mole) of 1-(2-chloro-4-methyl-5-methoxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 100 mL of methylene chloride at 10° C. was added dropwise 39.6 g (0.16 mole) of boron tribromide. The resultant mixture was stirred at room temperature for two days. This mixture was washed with 100 mL of water. The organic layer was dried with anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to leave an oil. This oil was stirred in petroleum ether:diethyl ether (90:10) forming a solid. The solid was collected by filtration to yield 10.5 g of 1-(2-chloro-4-methyl-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one (mp 154°-156° C.).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O.[NH2:14][NH2:15].Cl.Cl.NN.O>C(O)CO>[Br:1][C:2]1[C:3]([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:14][NH:15][CH:11]=1
Reactant: Oc1nc2ccccc2cc1Br
Reactant: NN
Agent: Cl
Solvent: OCCO
Solvent: O
Product: Brc1c[nH]nc1Nc1ccccc1

Procedure:
The bromohydroxyquinoline (1.97 g, 8.79 mmol) was dissolved in 21 ml of ethylene glycol and hydrazine hydrat (4.2 ml) was added. To this mixture were added 1.3 g (12.2 mmol) of hydrazine dihydrochloride, and the resulting mixture was heated to reflux and stirred under nitrogen. The resulting material was poured onto 300 ml of H2O. The mixture was extracted with CH2Cl2, basified with NaHCO3 and extracted further with CH2Cl2. The combined organic portions were washed with water, dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oil, yielding bromoanilinopyrazole (i.e., 3-(2-amino-5-bromophenyl)pyrazole).
Reaction SMILES: Cl.N[C@@H](C)[C@@H](C1C=CC(OC)=CC=1)O.[O:15]=[C:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:18][CH3:19]>>[NH2:20][C@@H:17]([CH2:18][CH3:19])[C@@H:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:15]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Agent: COc1ccc([C@@H](O)[C@H](C)N)cc1
Agent: Cl
Product: CC[C@H](N)[C@H](O)c1ccccc1

Procedure:
was synthesised in the same way as 90b from (S)-tert-butyl 1-oxo-1-phenylbutan-2-ylcarbamate (95c, 209 mg, 0.795 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>>[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[N:8]=1)(=[O:16])[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)(C)C(=O)CBr
Reactant: COc1ccc2c(C(=O)C(C)C)n[nH]c2c1
Product: COc1ccc2c(C(=O)C(C)C)nn(CC(=O)C(C)(C)C)c2c1

Procedure:
Reaction of 1-(6-methoxy-1H-indazol-3-yl)-2-methylpropan-1-one with 1-bromo-3,3-dimethylbutan-2-one using a procedure similar to that described in Example 3 Step A gave the title compound. Recrystallization from 2:1 hexanes and EtOAc gave fine needles. 1H NMR (CDCl3, 500 MHz) δ 8.25 (d, 8.9 Hz, 1H), 6.98 (dd, 2.0 & 8.9 Hz, 1H), 6.52 (d, 1.8 Hz, 1H), 5.37 (s, 2H), 3.87 (s, 3H), 3.86 (heptet, 6.9 Hz, 1H), 1.36 (s, 9H), 1.27 (d, 6.8 Hz, 6H). LC-MS: 3.70 min. (m/Z=317.1, 339.1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O.CC(O)=O.[Rh]>[C:21]([N:1]1[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH:3]([C:10]([OH:12])=[O:11])[CH2:2]1)([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [Rh]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)C2CCCCC12
Reaction time: 30 h
Yield: 34.2 %

Procedure:
A solution of 25 g (155 mmol) of indole-3-carboxylic acid in 1500 mL H2O and 150 mL HOAc was charged with 25 g of 5% Rh/Al2O3 and the mixture hydrogenated at 60 psi for 30 hr at 60° C. The mixture was filtered through Celite® and evaporated in vacuo to a dark oil which was treated with benzylchloroformate (26.35 g; 155 mmol) under basic conditions substantially according to the procedures of Example 1,A. The crude product crystallized out of hot CH2Cl2 /hexanes to yield 16.06 g (53 mmol; 49%) of N-Cbz-3-perhydroindolylcarboxylic acid as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:43]([OH:47])[CH2:44][CH2:45][OH:46]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:46][CH2:45][CH2:44][CH2:43][OH:47])[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCN(c3ccccc3)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(c3ccccc3)CC2)nc1OCCCO

Procedure:
The procedure described in Synthesis Example 3 was repeated by use of 4-t-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(4-phenylpiperazinyl)-4-pyrimidinyl]benzenesulfonamide and 1,3-propanediol, to thereby obtain the title compound as a pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:35])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:35])([CH:14]([F:16])[F:15])[N:13]=1
Reactant: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C(F)F)COCC(NC(=O)OC(C)(C)C)=N2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C(F)F)COCC(N)=N2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ((R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (23 g, 45.77 mmol) in DCM (615 ml) was added under argon TFA (23 ml, 302.27 mmol) below 25° C. After stirring for 18 h at 25° C., another TFA (12 ml, 151.13 mmol) was added. After stirring at 25° C. for another 6 h, cooled down to −5° C., quenched by 12.5% NH3 aqueous solution (110 ml). The DCM phase was collected and water (100 ml) was added. The DCM of the diphase solution was removed to provide a yellowish suspension. Filtered and dried to provide the title compound as yellowish crystals. ESIMS: 404 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): 10.72 (s, 1H), 8.96 (s, 1H), 8.38 (s, 1H), 7.99 (dd, 1H), 7.81 (m, 1H), 7.18 (d, 1H), 6.17 (br s, 2H), 6.15 (t, 1H), 3.98 (m, 4H), 2.53 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[F:36])=[O:27])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH:20]=O)=[O:16])[S:14][C:7]=12.Cl.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1.C(N(CC)CC)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][C:30]=1[F:36])=[O:27])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:42]3[CH2:43][CH2:44][CH2:45][CH:41]3[C:40]([O:39][CH3:38])=[O:46])=[O:16])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCC=O)sc34)cc2F)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CCCN1CCCNC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)c(F)c3)c2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]-N-(3-oxopropyl)thieno[3,2-b]pyridine-2-carboxamide (150 mg, 0.29 mmol) in 10 ml of anhydrous DMF was added L-proline methyl ester hydrochloride (96 mg, 0.58 mmol) and triethylamine (58 mg, 0.58 mmol). The mixture was stirred at room temperature under nitrogen for one hour, and 1M solution of sodium cyanoborohydride in THF (0.60 ml, 0.60 mmol) was added. The mixture was stirred for another hour, and poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give the crude product, which was purified by silica gel chromatography eluting with 2˜3% of methanol in chloroform to afford methyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-2-carboxylate as white solid. Yield: 90 mg, 50%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: N#Cc1ccccc1F
Reactant: Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc2c1ccn2-c1ccccc1C#N
Temperature: 150 °C
Yield: 85.1 %

Procedure:
4-Methyl-1H-indole (1.042 g, 7.94 mmol, 1.0 eq) was combined with 2-fluoro-benzonitrile (1.29 mL, 11.91 mmol, 1.5 eq) and potassium carbonate (2.195 g, 15.88 mmol, 2.0 eq) in DMF (7.94 mL, 1M) and heated at 150° C. for 4 hours. The reaction was then cooled to room temperature, diluted with water (20 mL), and extracted three times with ethyl acetate. The organic extracts were washed with water and aqueous saturated sodium chloride, dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on Merck silica gel (50 g) eluting with chloroform:hexane (1:3) followed by (1:1) to give the title compound (1.57 g, 85%).