Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=[O:3])C.[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1.O>[CH2:15]([O:14][C:12]([C:7]1[NH:8][C:9]([CH:11]=[O:3])=[CH:10][C:6]=1[CH3:5])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(C=O)cc1C
Temperature: -7.5 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
Acetic acid (360 mL) and water (300 ml) was added to a solution of ethyl 3,5-dimethyl-2-pyrrolecarboxylate (5 g, 29.9 mmol) in THF (300 mL). The mixture was cooled to −10 to −5° C. for 30 minutes. To the mixture was then added ceric ammonium nitrate (CAN, 67.21 g, 122.6 mmol) over a period of 30 minutes. The mixture was stirred at −10 to −5° C. for 1.5 hours. The reaction was diluted with water (800 mL) and extracted with dichloromethane (3×). The combined extracts were washed with sodium bicarbonate solution until the aqueous layer was basic, dried and concentrated. The residue was purified on a silica gel column (10% EtOAc in hexane) to give 2.4 g (44%) of 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.61 (br s, 1H, NH), 9.64 (s, 1H, CHO), 6.78 (s, 1H), 4.27 (q, J=7.17 Hz, 2H, OCH2CH3), 2.26 (s, 3H, CH3), 1.30 (t, J=7.17 Hz, 3H, OCH2CH3). MS 182 [M++1].
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[C:16]([OH:18])=O)[CH:7]=[CH:8][CH:9]=1.Cl.[CH3:25][O:26][C:27]([C:29]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:28].C(Cl)CCl>CN(C=O)C.C1C=CC2N(O)N=NC=2C=1>[CH3:25][O:26][C:27]([C:29]1([NH:36][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:13]([O:12][CH2:11][CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][CH2:2][OH:1])[CH:5]=3)[CH:14]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:28]
Reactant: COC(=O)C1(N)CCCCCC1
Reactant: COc1ccc(C(=O)O)cc1OCCc1cccc(CCO)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(CCO)c3)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.9 %

Procedure:
The compound of step 1 (280 mg, 0.885 mmol) was dissolved in DMF (1.3 ml) and HOBT (24 mg), 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (221 mg, 1.06 mmol) and EDIA (578 mg, 4.43 mmol) were added. The mixture was cooled in an ice bath and EDC (254 mg, 1.33 mmol) was added. The mixture was stirred at room temperature for 3 days and partitioned between EA and water. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound (120 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]2[CH3:16])[CH:3]=1.[F:17][C:18]1[CH:19]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CCO.C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][C@@H:11]3[CH3:16])[CH:3]=2)[CH:21]=[N:22][CH:23]=1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Reactant: CSc1nc(Cl)cc(N2CCOC[C@@H]2C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: COCCOC
Product: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Yield: 104 %

Procedure:
A mixture of (S)-4-(6-chloro-2-(methylthio)pyrimidin-4-yl)-3-methylmorpholine (intermediate 4) (850 mg, 3.0 mmol crude), 5-fluoropyridine-3-boronic acid pinacol ester (703 mg, 3.15 mmol), bis(diphenylphosphino)-ferrocenedichloropalladium(II):DCM complex (125 mg, 0.15 mmol) and sodium carbonate (954 mg, 9.0 mmol) in DME/H2O/EtOH (7:3:2, 12 mL) was heated in the microwave at 100° C. for 60 min. The mixture was then diluted with DCM (80 mL), washed with water (150 mL), the organic layer passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a dark brown oil (1.0 g) used without future purification.
Reaction SMILES: [CH:1]([O-])([O-])OC.[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[NH:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])(=[O:8])[CH3:7].N1C2C(=CC=CC=2)C=CC=1>CO>[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[NH:13][C:14](=[O:19])/[CH:15]=[C:16](\[O:18][CH3:1])/[CH3:17])(=[O:8])[CH3:7]
Reactant: COC([O-])[O-]
Reactant: CC(=O)CC(=O)Nc1cccc(NC(C)=O)c1
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CO/C(C)=C\C(=O)Nc1cccc(NC(C)=O)c1
Temperature: 140 °C
Yield: 58.5 %

Procedure:
11.7 g of methyl orthoformate were added to a solution of 23.4 g of m-acetamido-acetylacetanilide in 250 ml of anhydrous methanol and the mixture was refluxed for 3 hours and cooled. 0.6 ml of quinoline were added thereto and the methanol was distilled off under reduced pressure. Toluene was added to the residue and the mixture was heated at 140° C. for one hour while distilling a methanol-toluene azeotrope. The mixture was then concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with ethyl acetate yielded 14.5 g of m-acetamido-3-methoxy-crotonanilide melting at 167° C. Crystallization from acetone did not change the melting point.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10]1([CH3:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]1[C:19]([OH:21])=[O:20].[C:23]([S:26][CH2:27][CH2:28][C:29](Cl)=[O:30])(=[O:25])[CH3:24].Cl>C(Cl)Cl>[C:23]([S:26][CH2:27][CH2:28][C:29]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH3:22])([CH3:9])[CH:11]1[C:19]([OH:21])=[O:20])=[O:30])(=[O:25])[CH3:24]
Reactant: CC1(C)c2ccccc2NC1C(=O)O
Reactant: CC(=O)SCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(=O)N1c2ccccc2C(C)(C)C1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.93 g of triethylamine are added to the suspension of 0.7 g of 3,3-dimethylindoline-2-carboxylic acid hydrochloride in 20 ml of methylene chloride and the resulting solution is cooled to -10°. The solution of 0.51 g of 3-acetylthiopropanoyl chloride in 5 ml of methylene chloride is added dropwise and the mixture stirred at -5° to -10° for 1 hour and at room temperature for 3 hours. It is cooled to 0° and treated with 10 ml of 3N hydrochloric acid. The organic layer is separated and the aqueous solution further extracted with methylene chloride. The combined methylene chloride solutions are dried and evaporated, to give the 1-(3-acetylthiopropanoyl)-3,3-dimethylindoline-2-carboxylic acid as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[CH2:12]([O:11][P:10]([O:14][CH2:15][CH3:16])[O:17][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:13]
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(OCC)OCc1ccc(Br)cc1
Temperature: 140 °C

Procedure:
A reaction vessel was loaded with 4-bromobenzyl bromide and 1 equivalent of triethyl phosphite. The content of the chamber was heated to 140° C. for 6 hours with stirring. Excess triethyl phosphite was removed from the mixture by vacuum distillation to yield phosphorous acid-4-bromobenzyl diethylester. One equivalent of cyclohexanone and 1.2 equivalent of sodium hydride in a mixed solvent of toluene-dimethylsulfoxide were reacted with the phosphorous acid-4-bromobenzyl diethyl ester whith heating moderately.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@@H:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[CH:22]1([CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C@@H:12]3[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH2:23][CH2:24]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@@H](N3CCN(CC4CC4)CC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1

Procedure:
8.5 g (20 mmol) of cis-dibenzyl-[4-(4-cyclopropylmethyl-piperazin-1-yl)-cyclohexyl]-amine are dissolved in 170 mL MeOH and hydrogenated on 1.7 g Pd/C (10%) at 30-50° C. The solvent is eliminated in vacuo and the residue is crystallised from ethanol and conc. HCl.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:12]1([CH:18]([C:21]2[CH:26]=[CH:25][N:24]=[N:23][CH:22]=2)[CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][N:24]=[N:23][CH:22]=1)=[O:6]
Reactant: NCC(c1ccccc1)c1ccnnc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccccc1)c1ccnnc1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-phenyl-2-(pyridazin-4-yl)ethanamine. LCMS (MH+): m/z=372.1, tR (minutes, Method G)=2.05
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH2:36]Cl)[CH:31]=1>CN(C)C=O>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:31]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: ClCc1cc(Cl)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4cc(Cl)ccn4)cc3)no2)c(N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. An N,N-dimethylformamide (1 mL) solution of 4-chloro-2-chloromethyl-pyridine (34.3 mg, 0.21 mmol) described in Manufacturing Example 51-1-2 was added to a suspension of this solid in N,N-dimethylformamide (1 mL), which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:2), and then further purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (5.1 mg, 12%) as a trifluoro acetic acid salt.
Reaction SMILES: [C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH3:26])[CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.CCCCCC>C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][Br:27])[CH:20]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)[Si](Oc1ccc(Cl)c(CBr)c1)(c1ccccc1)c1ccccc1

Procedure:
tert-Butyl(4-chloro-3-methylphenoxy)diphenylsilane (88.69 g, 0.233 mol), N-bromosuccinimide (49.8 g, 0.279 mol), and AIBN (3.82 g, 0.023 mol) were heated at reflux in CCl4 (500 mL) for 7 h. The reaction mixture was concentrated in vacuo, dissolved in 10% EtOAc/hexane, the succinimide filtered off, and the filtrate concentrated in vacuo to give a mixture of the mono- and di-bromides. Chromatography (SiO2)(100% hexane) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([Br:11])[CH:5]=1.[N:13]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.Cl.ClCCl>[Br:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][NH2:13])[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1ccc(N)c(Br)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(NN)c(Br)c1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
Methyl-4-amino-3-bromobenzoate (32 g, 139 mmol) is combined with 250 mL conc. hydrochloric acid and cooled to −10° C. A solution of sodium nitrite (10.2 g, 146 mmol) in 120 mL water is added dropwise such that the temperature does not exceed −5° C. After 40 min stirring at −10° C. a solution of tin(II)chloride dihydrate (128 g, 556 mmol) in 130 mL conc. hydrochloric acid is added dropwise to the suspension, while the reaction temperature does not exceed −5° C. The thick liquid suspension is stirred for 1.5 h at RT, before being adjusted to pH 10 with NaOH (12 N). The reaction mixture is combined with 500 mL dichloromethane and water and after 30 min stirring it is filtered. The filter cake is combined with 300 mL dichloromethane and 100 mL water and refluxed for 30 min. After filtration the filtrate is extracted with chloroform. The combined organic phases are dried on magnesium sulphate, filtered and evaporated to dryness. Yield: 34 g.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([O:25]C)=O)[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([CH3:28])=[CH:30][CH:31]=3)=[O:25])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(CNC(=O)Cn2ncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc32)cc1

Procedure:
Example 126 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate Example 117) and 4-methylbenzylamine to give the title compound (0.010 g)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:19])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH:19][S:21]([CH3:20])(=[O:23])=[O:22])=[N:10][NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as set forth in Example 2 (200 mg, 0.77 mmol) and methanesulfonyl chloride (90 mg) in pyridine (5 ml) was stirred at room temperature overnight. The pyridine was removed in vacuo and the residue was treated with methylene chloride and water. The resultant precipitate was filtered to give N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide. Additional N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide was contained in the methylene chloride layer. The methylene chloride was stripped in vacuo and the residue purified by chromatography on silica gel using mixtures of ethyl acetate and methanol as eluents. The purified N-[4(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]methanesulfonamide had m.p. 168-170° C.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[CH:10]1([C:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:46])[N:23]([C:39]5[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=5)[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[N:25]4)=[CH:20][CH:19]=3)ON=2)[CH2:12][CH2:11]1>>[CH:10]1([C:13]2[O:3][N:2]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([C:22](=[O:46])[N:23]([C:39]5[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=5)[C:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[N:25]4)=[CH:20][CH:19]=3)[CH:17]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)CCCCc1nc2cc(-c3cc(C4CC4)no3)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCCCc1nc2cc(-c3cc(C4CC4)on3)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 110 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A solution of 8A (27 mg, 0.053 mmol) and hydroxylamine hydrochloride (4.3 mg, 0.062 mmol) in pyridine (1 mL, 10 mmol) was stirred at 60° C. for 7 h. The reaction was then stirred at at 110° C. for 16 h. The reaction was quenched with 0.1N HCl and diluted with DCM. The organic layer was removed and the aqueous phase was extracted with DCM (3×). The combined organics were concentrated. The residue was purified by flash chromatography (0% to 20% (12 min) to 70% (10 min) EtOAc/hexanes) to yield an inseparable mixture of tert-butyl 5-(7-(3-cyclopropylisoxazol-5-yl)-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pentanoate and regioisomer tert-butyl 5-(7-(5-cyclopropylisoxazol-3-yl)-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)pentanoate (17 mg; Yield=63%), MS (M+H)=504.3.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:22]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCCCCCCCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCCCCCCCC=C[Sn](CCCC)(CCCC)CCCC
Temperature: 50 °C
Yield: 95.8 %

Procedure:
A solution of 1-dodecyne (50.0 g), tributyltinhydride (109.4 g), and azobisisobutyronitrile (100 mg) was stirred at 95° C. for 3 hrs. The reaction mixture was cooled to 50° C. and evaporated. The residue was filtered through a column of silica, using hexane as the eluent. The appropriate fractions were collected and evaporated. The residue was dried under vacuum to give 131.7 g (96.0%) of tri-n-butyl-1 -dodecenylstannane.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:19][CH3:20])[CH2:6][C:5]([C:13](OC(C)C)=[O:14])([C:7](OC(C)C)=[O:8])[CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:8][CH2:7][C:5]1([CH2:13][OH:14])[CH2:4][C:3]([O:2][CH3:1])([O:19][CH3:20])[CH2:6]1
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COC1(OC)CC(CO)(CO)C1
Yield: 41.2 %

Procedure:
Diisopropyl 3,3-dimethoxy-cyclobutane-1,1-dicarboxylate (6.0 g, 20.8 mmol), prepared as described by P. E. Pigou and C. H. Schiesser, J Org Chem, 53, 3841-3 (1988), was dissolved in 200 mL of anhydrous diethyl ether and the ether solution was cooled to 0° C. with stirring under a nitrogen atmosphere. Lithium aluminum hydride (1.6 g, 42 mmol) was added to the ether solution in portions and the reaction mixture was stirred at 0° C. for 0.5 h. The reaction was then quenched by the addition of 1.6 mL of water, followed by 1.6 mL of 15% aqueous sodium hydroxide solution and 4.8 mL of water. The reaction mixture was filtered, the filter cake washed with diethyl ether and the combine ether filtrates were concentrated under reduced pressure. The residue (3.0 g) was dissolved in 2 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @ 2-3 psi with 200 mL of acetone:hexane (1:2 v/v), followed by 200 mL of acetone:hexane (1:1 v/v) to give 1.51 g (41% yield) of the title compound; MS DCI/NH3M-Z: 194 (M+NH4)+ ; 1H NMR (CDCl3) δ 1.99 (s, 4H), 2.35 (t, 2H-OH), 3.16 (s, 6H), 3.77 (d, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C#N
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(C)no3)c2)cc1C#N

Procedure:
The title compound was prepared from [2-amino-4-cyano-5-(methyl-propyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J29) (304 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (370 mg, 70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:12][C:4]1[N:3]=[C:2]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Reactant: COc1ccc(CN)cc1
Solvent: c1ccncc1
Product: COc1ccc(CNc2cc(C(F)(F)F)cc(Cl)n2)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethyl-pyridine (5.04 g, 23.3 mmol) in pyridine (10 mL) was treated with 4-methoxybenzylamine (9.19 mL, 70.0 mmol) and heated to 110° C. for 26 h. The mixture was cooled, and pyridine (8 mL) was removed in vacuo. The remaining material was diluted with water (50 mL) and extracted twice with EtOAc (75 mL, and 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 115-g SEPRA Si 35 SPE column (Flow rate=35 mL/min; Eluent=EtOAc-hexanes, 1:99 for 15 min, then 1:99 to 1:9 over 40 min, 1:9 for 2 min, then 1:9 to 1:4 over 20 min) to yield (6-chloro-4-trifluoromethyl-pyridin-2-yl)-(4-methoxy-benzyl)-amine as a colorless oil, which solidified upon standing. 1H-NMR (400 MHz, CDCl3) δ: 7.26 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.77 (s, 1H), 6.44 (s, 1H), 5.21 (br. s., 1H), 4.44 (d, J=5.6 Hz, 2H), 3.80 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calculated for C14H12N2OClF3: 317.1 (M+H); Measured: 317.1.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]3[CH:10]=[CH:9][C:8]([C:24]#[N:25])=[CH:7][C:6]=3[C:5]=2[CH2:4]1.C(N(CC)CC)C.[CH:33]1([S:36](Cl)(=[O:38])=[O:37])[CH2:35][CH2:34]1>ClCCl>[C:24]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:13]1[CH2:14][CH2:15][CH:3]([NH:2][S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])[CH2:4][C:5]2=1)#[N:25]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(N)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NS(=O)(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
Combine 6-amino-9-(3-fluoro-benzyl)6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile, hydrochloride salt (Preparation 54) (125 mg, 0.35 mmol) and triethylamine (0.195 mL, 1.4 mmol) in dichloromethane (3 mL) under nitrogen. Add cyclopropylsulfonylchloride (51 mg, 0.36 mmol) in dichloromethane (1 mL). Stir for 18 h at room temperature. Purify the reaction solution directly by flash chromatography, eluting with 20% ethyl acetate/hexane and then a gradient up to 50% ethyl acetateihexane to obtain 80 mg. Triturate in diethyl ether to obtain 61 mg (41%) of a tan solid. MS (ES): m/z 424 (M+1), 422 (M−1); 1H NMR(DMSO-d6): δ 7.98 (d, 1H, J=1.3 Hz), 7.56 (d, 1H, J=8.4 Hz), 7.41 (dd, 1H, J=8.4, 1.3 Hz), 7.36-7.30 (m, 2H), 7.07 (dt, 1H, J=8.7, 2.5 Hz), 6.88 (d, 1H, J=9.7 Hz), 6.83 (d, 1H, J=7.9 Hz), 5.42 (d, 2H, J=5.3 Hz), 3.68 (m, 1H), 3.10 (dd, 1H, J=15.4, 5.3 Hz), 2.90-2.81 (m, 1H), 2.79-2.61 (m, 3H), 2.13 (m, 1H), 1.86 (m, 1H), 0.98-0.91 (m, 4H).