Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Si]([O:34][CH2:35][CH2:36][N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:40]4[CH:39]=[N:38][N:37]([CH2:36][CH2:35][OH:34])[CH:41]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cnn(CCO)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was concentrated. The residue was treated with methanol. The solid was filtered off. The filtrate was concentrated. The resulting residue was dissolved in 1.5 ml of 1% HCl ethanol solution, and stirred at r.t. overnight. Then it was purified with RP-HPLC (pH=10) to afford the desired product (4.6 mg). LCMS (M+H)+: m/z=449.3.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)c(Cl)c4)cc3CC[C@@H]12
Yield: 73.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-chloro-4-fluorophenylboronic acid (136 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 170 mg (73%) of the title compound as a white solid. mp 114°-116°. FDMS: m/e=357. α[D]589 =+86.00 (c=1.00, methanol).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11](Br)=[CH:12][N:13]=2)[N:10]=1)[CH:2]=[CH2:3].[CH2:15]([NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20])[CH:16]=[CH2:17].C(O)CCC.C(=O)([O-])[O-].[Na+].[Na+]>O.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]>[CH2:15]([NH:18][C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([C:11]2[N:9]3[N:10]=[C:5]([NH:4][CH2:1][CH:2]=[CH2:3])[CH:6]=[CH:7][C:8]3=[N:13][CH:12]=2)=[CH:23][CH:22]=1)[CH:16]=[CH2:17]
Reactant: C=CCNC(=O)c1ccc(B(O)O)cc1
Reactant: C=CCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCCCO
Solvent: O
Product: C=CCNC(=O)c1ccc(-c2cnc3ccc(NCC=C)nn23)cc1
Temperature: 100 °C

Procedure:
To a mixture of N-allyl-3-bromoimidazo[1,2-b]pyridazin-6-amine (365 mg, 1.44 mmol), (4-(allylcarbamoyl)phenyl)boronic acid (615 mg, 3.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (62 mg, 0.085 mmol) was added n-butanol (3 mL) and 2 M aqueous sodium carbonate (2 mL). The resulting mixture was heated at 100° C. for 5 h. The reaction was then diluted with water, extracted with ethyl acetate, and purified by silica gel column (10% methanol in ethyl acetate) followed by preparative HPLC (acetonitrile/aqueous ammonium formate, Sunfire column) to afford N-allyl-4-(6-(allylamino)imidazo[1,2-b]pyridazin-3-yl)benzamide as a white solid: 1H NMR (METHANOL-d4) δ: 8.30-8.33 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.4 Hz, 2H), 7.67 (d, J=9.6 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 5.9-6.2 (m, 2H), 5.1-5.4 (m, 4H), 4.00 (m, 4H); LRMS (ESI) m/z 334.2 [(M+H)+, calcd for C19H19N5O 333.4]
Reaction SMILES: [C:1]1([C:7]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:11][C:10](=[O:12])[N:9]([CH2:13][OH:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22][CH2:23][C:24](Cl)=[O:25].Cl>C(OCC)C>[Br:22][CH2:23][C:24]([O:14][CH2:13][N:9]1[C:8](=[O:15])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:11][C:10]1=[O:12])=[O:25]
Reactant: O=C(Cl)CBr
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1CO
Agent: Cl
Solvent: CCOCC
Product: O=C(CBr)OCN1C(=O)NC(c2ccccc2)(c2ccccc2)C1=O
Temperature: 0 °C

Procedure:
5,5-Diphenyl-3-hydroxymethyl-2,4-imidazolidinedione (2 g, 0.0071 mol) was dissolved in bromoacetylchloride (15 g, 8 ml, 0.096 mol) by heating in an oil bath (70°-80° C. bath temperature) for about 15 minutes, until the formation of HCl ceased. The mixture was cooled and 30 ml of ethyl ether were added. White crystals formed. The mixture was cooled to 0° C., then the crystals were removed by filtration ad dried over P2O5. Yield: 2.15 g (75%), m.p. 179°-183° C. Anal. calc. for C18H15N2O4Br: C, 53.61; H, 3.75; N, 6.95; Br, 19.82. Found: C, 53.60; H, 3.79; N, 6.92; Br, 19.90. The product has the formula: ##STR1543##
Reaction SMILES: [C:1]1([C@:7]([C:10]([OH:12])=[O:11])([CH3:9])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].C[NH+](C)C.[C:18]([O:22][C:23](=O)[O:24]C(C)(C)C)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:22][C:23]([NH:8][C@@:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:10]([OH:12])=[O:11])[CH3:9])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C[C@@](N)(C(=O)O)c1ccccc1
Agent: C[NH+](C)C
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@](C)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 500 mg of 2-phenyl-D-alanine (3.02 mmol) and trimethylammonium hydroxide (aqueous solution 10%, 2.8 mL, 3.02 mmol) in 15 mL of acetonitrile, diterbutylcarbonate (1.047 g, 4.8 mmol) was added and the mixture was stirred at room temperature for 2 days. The solvent was then removed under vacuo, the residue was dissolved in water and washed with diethylether. The aqueous layer was acidified to pH=3-4 with citric acid and the product was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with water, dried over Na2SO4 and evaporated. The title product was recovered as white solid (630 mg, yield 78%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]2[C:8](=[C:9]([CH2:24][CH2:25][CH3:26])[C:10]3[O:17][C:16]([C:18]([O:20]CC)=[O:19])=[CH:15][C:14](=[O:23])[C:11]=3[CH:12]=2)[N:7]=[C:6]([C:27]([O:29]CC)=[O:28])[CH:5]=1)[CH3:2].[Na:32][Na].ClC1C2C=C(OC)C3C(=O)C=C(C([O-])=O)OC=3C=2N=C(C([O-])=O)C=1.[Na+].[Na+]>>[CH2:1]([NH:3][C:4]1[C:13]2[C:8](=[C:9]([CH2:24][CH2:25][CH3:26])[C:10]3[O:17][C:16]([C:18]([O-:20])=[O:19])=[CH:15][C:14](=[O:23])[C:11]=3[CH:12]=2)[N:7]=[C:6]([C:27]([O-:29])=[O:28])[CH:5]=1)[CH3:2].[Na+:32].[Na+:32]
Reactant: [Na][Na]
Reactant: CCCc1c2nc(C(=O)OCC)cc(NCC)c2cc2c(=O)cc(C(=O)OCC)oc12
Agent: COc1cc2c(Cl)cc(C(=O)[O-])nc2c2oc(C(=O)[O-])cc(=O)c12
Agent: [Na+]
Product: CCCc1c2nc(C(=O)[O-])cc(NCC)c2cc2c(=O)cc(C(=O)[O-])oc12

Procedure:
The product of step (c) was hydrolysed to the disodium salt by the method of Example 3 (g) to afford a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O.BrBr>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: BrBr
Product: O=C(Cl)Cc1ccc(Cl)cc1

Procedure:
For example, 4-chlorophenylacetic acid 1, can be treated with thionyl chloride to activate the carboxylic acid. This can then be treated with bromine to form 4-chlorophenylacetyl chloride. The esterification is conveniently carried out with (S)—N,N-tetramethylenelactamide 2. This reaction sequence is particularly advantageous as the reactions are conveniently carried out in one reaction vessel with only one isolation step. The displacement reaction of ester 3 with 3-trifluoromethylphenol 4 in the presence of potassium hydroxide gives α-(phenoxy)phenylacetic acid ester 5. Hydrolysis of the α-(phenoxy)phenylacetic acid ester 5 with lithium hydroxide afforded α-(phenoxy)phenylacetic acid 6. In this manner, (4-chlorophenyl)-(3-trifluoromethylphenoxy)-acetic acid, i.e., CPTA, can be prepared in five steps in about 73% yield following crystallization from heptane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1OC2C=CC=CC=2N=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[Br-]>CCOC(C)=O>[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([CH3:33])[CH:22]([C:24]1[O:8][C:7]2[CH:6]=[C:5]([CH3:9])[CH:4]=[CH:3][C:2]=2[N:1]=1)[OH:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O)c1nc2ccccc2o1
Reactant: Cc1ccc(N)c(O)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(C(O)[C@H](C)NC(=O)OCc3ccccc3)oc2c1
Yield: 71 %

Procedure:
This material was prepared as a 1:1 mixture of isomers in 71% yield from the above cyanohydrin (1.44 g, 6.15 mmol) and 6-amino-m-cresol (832 mg, 6.77 mmol) using the procedure described above for compound 16. An analytical sample was obtained by recrystallization from EtOAc in hexanes (8:1 mixture of isomers). mp: 108-109° C.; IR (KBr) υ 1692 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.54 (d, J=8.3 Hz, 1H), 7.36-7.10 (m, 7H), 5.40 and 5.32 (d, J=8.9 and 8.9 Hz, 1H), 5.14-4.85 (m, 3H), 4.42-4.28 (m, 2H), 2.47 (s, 3H), 1.33 and 1.14 (2×d, J=6.7 and 6.7 Hz, 3H); 13C-NMR (100.6 MHz, CDC13) δ 165.08, 156.11, 151.24, 137.95, 136.28, 135.76, 128.52, 128.16, 127.99, 127.90, 125.89, 125.79, 119.38, 119.20, 111.09, 70.99, 70.69, 66.99, 66.76, 50.55, 50.26, 21.70, 17.29, 15.38; FAB MS m/z: 341 (MH+); HRMS calcd for C19H21N2O4 (MH+) 341.1501, found: 341.1490; Anal (C19H20N2O4) C, H, N.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([C:7]1[NH:8][N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])[CH3:3].[CH2:17](I)[CH3:18]>C(O)C.C([O-])C.[Na+]>[CH2:2]([O:4][C:5]([C:7]1[N:8]([CH2:17][CH3:18])[N:9]=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6])[CH3:3]
Reactant: CCI
Reactant: CCOC(=O)c1cn[nH]c1C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnn(CC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.9 %

Procedure:
Sodium ethanolate solution was freshly prepared by dissolving sodium (240 mg) in ethanol (30 ml). 2H-Pyrazole-3,4-dicarboxylic acid diethyl ester (800 mg, 3.77 mmol) was dissolved in this sodium ethanolate solution (11 ml) and stirred for 10 min (r.t.), before ethyl iodide (1.4 g, 9 mmol) was added dropwise. After the completion of the addition, the mixture was heated to reflux until all starting material was consumed (1 h). The solvent was then evaporated, the residue was taken up in ethyl acetate and washed (water). The organic layer was dried (Na2SO4), evaporated, and the title compound (280 mg, 31%) was isolated from the mixture by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). (The regioisomeric 1-ethyl-1H-pyrazole-3,4-dicarboxylic acid diethyl ester can also be isolated, and can be distinguished from the desired product by NOE-1H-NMR.) MS (m/e)=241.1 [M+H+].
Reaction SMILES: [NH3:1].[CH3:2][O:3][CH:4]([O:9][CH3:10])[CH2:5][N:6]=[C:7]=[S:8]>CO>[CH3:2][O:3][CH:4]([O:9][CH3:10])[CH2:5][NH:6][C:7]([NH2:1])=[S:8]
Reactant: N
Reactant: COC(CN=C=S)OC
Solvent: CO
Product: COC(CNC(N)=S)OC

Procedure:
Methanol (200 mL) was saturated with ammonia and stirred with isothiocyanatoacetaldehyde dimethyl acetal (5.0 g) for 2 h. The mixture was concentrated and the residue was chromatographed (silica gel, 5% methanol/dichloromethane) to give the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][N:5]([C:7](=[O:27])[C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][C:9]=2[N+:24]([O-])=O)[C@H:4]([CH:28]=O)[CH2:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(Cl)Cl.CO.C(Cl)(C)=O>C1COCC1.O>[CH3:15][O:14][C:12]1[C:11]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][C:9]2[N:24]=[CH:28][C@@H:4]3[CH2:3][C:2](=[CH2:1])[CH2:6][N:5]3[C:7](=[O:27])[C:8]=2[CH:13]=1
Reactant: C=C1C[C@@H](C=O)N(C(=O)c2cc(OC)c(OCc3ccccc3)cc2[N+](=O)[O-])C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: C=C1C[C@H]2C=Nc3cc(OCc4ccccc4)c(OC)cc3C(=O)N2C1
Yield: 70 %

Procedure:
To a solution of (2S)-4-(methylene)-1-[5-methoxy-2-nitro-4-(phenylmethoxy)benzoyl]-2-pyrrolidinecarboxaldehyde (1.0 equivalent) in THF/H2O (v/v, 1.7:1, 0.03 M) was added sodium hydrosulfite (5˜8 equivalent) in portions within 2 minutes at room temperature. The mixture was further stirred for 6˜20 hours and monitored by TLC (hexanes/AcOEt 1:2 and CH2Cl2/MeOH 5:1). After the aldehyde was almost consumed, the reaction was quenched with methanol (about same volume as THF used). The solvents were removed by rotary evaporation in vacuo (temperature <40° C.) and the remainder solid was put on high vacuum to make it completely dry. The solid was suspended in anhydrous methanol (0.03 M) and AcCl (8˜10 equivalent) was added dropwise at room temperature. After stirred for 15 minutes, the cloudy solution was filtered and the solid was washed with anhydrous methanol. The clear yellow filtrate was stirred at room temperature for 1 to 2 hours and was quenched with saturated sodium bicarbonate. After most of the methanol was removed by rotary evaporation, the remainder was diluted with dichloromethane and water. The aqueous layer was extracted with AcOEt. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The solvents were removed and the residue was purified by flash chromatography (hexanes/AcOEt, 1:3, 1:5) to give (11aS)-7-methoxy-2-methylene-8-(phenylmethoxy)-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one in 70% to 85% yield. The NMR spectra are consistent with the literature reported. MS (ESI): m/z 371.2 (M+Na)+. MS (ESI, with CH3OH): m/z 403.3 (M+CH3OH+Na)+. MS (ESI, with H2O): m/z 389.2 (M+H2O+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.BrC1C=C(C(OC)=O)C2C(C=O)=NNC=2C=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH2:65][CH2:66][C:67]1[C:68](=[O:75])[NH:69][C:70]([CH3:74])=[CH:71][C:72]=1[CH3:73]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:65][CH2:66][C:67]2[C:68](=[O:75])[NH:69][C:70]([CH3:74])=[CH:71][C:72]=2[CH3:73])=[O:17])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1nn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: COC(=O)c1cc(Br)cc2[nH]nc(C=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-bromo-1-isopropyl-3-methyl-1H-indazole-4-carboxylic acid, 1 (6.5 g, 21.88 mmol) in DCM (250 mL) was added EDC.HCl (5.01 g, 26.23 mmol), HOBt (3.545 g, 26.20 mmol) followed by diisopropyl ethyl amine (14.11 g, 109.37 mmol) and stirred at room temperature for 15 min. To the resulting mixture, 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (3.32 g, 21.84 mmol) followed by DMAP (catalytic amount) was added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with DCM (300 mL) and washed with 1N HCl solution (250 mL), saturated NaHCO3 solution (250 mL) and brine solution. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether (100 mL), filtered, and dried to afford 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide as an off white solid (5.5 g, 58%). 1H NMR (DMSO-d6, 400 MHz): δ 1.412 (d, J=6.4 Hz, 6H), 2.112 (s, 3H), 2.215 (s, 3H), 2.383 (s, 3H), 4.319 (d, J=5.2 Hz, 2H), 4.907-4.972 (m, 1H), 5.864 (s, 1H), 7.129 (d, J=1.2 Hz, 1H), 8.011 (d, J=1.2 Hz, 1H), 8.473 (t, J=5 Hz, 1H), 11.479 (brs, 1H). LCMS (ES+): 431.02 [M+H].
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>>[CH3:13][O:12][C:8]([CH2:9][CH2:10][N:7]([CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])=[O:11]
Reactant: NCc1ccco1
Reactant: C=CC(=O)OC
Product: COC(=O)CCN(CCC(=O)OC)Cc1ccco1

Procedure:
48.56 Grams of furfurylamine and 200 milliliters of methyl acrylate are refluxed together for 84 hours. The excess methyl acrylate is evaporated off to give 133.46 grams of N,N-di(2-methoxycarbonylethyl)furfurylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][C:20]1=[O:29]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1Cc2ccccc2NC1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1Cc2ccccc2NC1=O

Procedure:
Following General Procedure A above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1,2,3,4-tetrahydroquinolin-2-one (Example 5-A), the title compound was prepared as a mixture of diasteromers. The reaction was monitored by tlc on silica gel (Rf=0.38 in 25% ethyl acetate/hexanes) and purification was by flash chromatography using 25% ethyl acetate/hexanes as the eluant.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][C:6]2=[C:7]([C:12]([OH:14])=O)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:30](=[N:33]O)([NH2:32])[CH3:31]>O1CCOCC1>[CH3:17][C:2]1([CH3:1])[CH2:15][C:6]2=[C:7]([C:12]3[O:14][N:33]=[C:30]([CH3:31])[N:32]=3)[S:8][C:9]([S:10][CH3:11])=[C:5]2[C:4](=[O:16])[CH2:3]1
Reactant: CSc1sc(C(=O)O)c2c1C(=O)CC(C)(C)C2
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CSc1sc(-c2nc(C)no2)c2c1C(=O)CC(C)(C)C2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a solution of 6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one-1-carboxylic acid (1.0 g, 3.7 mmol) in dioxan (90 mL) was added carbonyldiimidazole (0.6 g, 3.7 mmol) and the mixture stirred at 20° C. for 30 min. Acetamide oxime (0.41 g, 5.5 mmol) was added and the mixture was heated at 100° C. for 48 h. The solution was evaporated to dryness and the residue was purified by chromatographed on silica gel, eluting with ethyl acetate:hexane (2:3) to yield the title compound as a pale yellow solid (0.1 g, 9%). mp 177-180° C. Found: C, 54.90; H, 5.05; N, 8.71%. C14H16N2O2S2 requires: C, 54.52; H, 5.23; N, 9.08%. 1HNMR (250 MHz, CDCl3) δ 1.11 (6H, s), 2.45-2.47 (5H, m), 2.65 (3H, s), 3.11 (2H, s). MS (ES+) 309 (M+1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[CH:5]([OH:7])[CH3:6].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>CN(C=O)C.O>[F:3][C:4]([F:9])([F:8])[CH:5]([O:7][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH3:6]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C#N)cc1)C(F)(F)F
Temperature: 50 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
Sodium hydride (297 mg, 12.4 mmol) was suspended in DMF (3 ml) at 0° C. 1,1,1-trifluoropropan-2-ol (500 μl, 5.52 mmol) was added slowly and the reaction was stirred for 15 minutes at 0° C. before addition of 4-fluorobenzonitrile (500 mg, 4.13 mmol). The mixture was allowed to reach room temperature and was then stirred at 50° C. for 20 hours. The reaction was cooled, diluted with water (75 ml) and extracted with EtOAc (4*20 ml). Combined organics were washed with water (20 ml), dried over MgSO4 and evaporated. The product was purified by flash chromatography using pet.ether/EtOAc (8:1) as eluent to give 690 mg (78%) of the title compound as a clear liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: Cc1cccc(C)c1O
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: Cc1cccc(C)c1Oc1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2

Procedure:
The title compound was prepared from 2,6-dimethylphenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 252.7–258.6° C. 1H NMR (acetone-d6/300 MHz) 7.88 (s, 1H), 7.71 (s, 1H), 7.22 (m, 3H), 6.04 (s, 1H), 5.77 (q, 1H, J=7.0 Hz), 2.13 (s, 6H). 19F NMR (acetone-d6/282 MHz) −79.6 (d, J=7.2 Hz). FABLRMS m/z 397 (M−H). ESHRMS m/z 397.0450 (M−H, Calc'd 397.0454). Anal. Calc'd for C19H14ClF3O4: C, 57.23; H, 3.54; Cl, 8.89. Found: C, 57.21; H, 3.56; Cl, 8.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([CH3:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[CH:30]=[C:29]([CH3:31])[S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.