Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:14][CH:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCCCCl)c2)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2cccc(OCCCN3CCCCC3)c2)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 139 using tert-butyl N-[3′-(3-chloropropoxy)biphenyl-4-ylmethyl]carbamate instead of 3-(3-chloropropoxy)-4-phenylbenzonitrile and piperidine instead of pyrrolidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][NH:22]3)=[O:16])[CH2:7][CH2:6]2.[C:27](Cl)(=[O:29])[CH3:28].C(OCC)(=O)C>N1C=CC=CC=1>[C:27]([N:22]1[C:23]2[C:19](=[C:18]([NH:17][C:15]([NH:14][CH:8]3[C:9]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[CH:10]=4)[CH2:6][CH2:7]3)=[O:16])[CH:26]=[CH:25][CH:24]=2)[CH:20]=[N:21]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1OC)C(NC(=O)Nc1cccc3[nH]ncc13)CC2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc2c(cc1OC)C(NC(=O)Nc1cccc3c1cnn3C(C)=O)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 38 %

Procedure:
To the solution of 1-(5,6-dimethoxy-indan-1-yl)-3-(1H-indazol-4-yl)-urea (0.1 g, 0.28 mmol) in pyridine (2 mL) was added acetyl chloride (0.5 mL) and mixture stirred for 15 hours at ambient temperature. The mixture was suspended with ethyl acetate and filtered. The precipitate was triturated with ether twice and dried to obtain 42 mg (38%) of desired product as a yellow solid. NMR (DMSO-d6): 8.98 (s, 1H), 8.72 (s, 1H), 7.60 (d, J 7.5 Hz, 1H), 7.32-7.18 (m, 2H), 6.90 (d, J 8Hz, 2H), 6.53 (d, J 8 Hz, 1H), 5.16 (m, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.00-2.70 (m, 5H), 2.43 (m, 1H), 1.82 (m, 1H). MS (DCI): 395 (M+1). Elemental: Calculated for C18H18N4O2.0.2 H2O: C 63.37, H 5.67, N 14.08; Found: C 63.07, H 5.49, N 13.94.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH:24](/B(O)O)=[CH:25]\[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O1CCOCC1>CO.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]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: OB(O)/C=C/c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(/C=C/c3ccccc3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), (E)-styrylboronic acid (45 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 50-80% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (5.8 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 3.85 (s, 3H) 6.59 (d, J=2.27 Hz, 1H) 7.22 (dd, J=8.08, 1.77 Hz, 1H) 7.55 (t, J=7.83 Hz, 1H) 7.59-7.70 (m, 4H) 7.98-8.09 (m, 3H) 8.20 (d, J=2.02 Hz, 1H) 11.27 (s, 1H). ESI-MS: m/z 399.3 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13](C1C=CC=CC=1)[C:14](=[O:16])[O-])(=[O:12])=[O:11].[NH2:24][C:25]1[N:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([O:33][CH3:34])[N:26]=1>O1CCOCC1.C(OCC)(=O)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:24][C:25]1[N:30]=[C:29]([CH2:31][CH3:32])[N:28]=[C:27]([O:33][CH3:34])[N:26]=1)=[O:16])(=[O:11])=[O:12]
Reactant: CCc1nc(N)nc(OC)n1
Reactant: O=C([O-])N(c1ccccc1)S(=O)(=O)c1ccccc1OC(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)nc(OC)n1
Temperature: 0 °C
Yield: 80.5 %

Procedure:
A solution of 5.4 g of N-(2-difluoromethoxyphenylsulfonyl)phenylcarbamate and 2.42 g of 2-amino-4-ethyl-6-methoxy-1,3,5-triazine in 60 ml of dioxane is refluxed for 5 hours and then poured into 600 ml of ice-water. The precipitate is taken up in ethyl acetate. The ethyl acetate phase is washed with water, dried and concentrated. The residual oil is dissolved in ethyl acetate and washed 5 times with saturated sodium bicarbonate solution. The combined aqueous phases are acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is dried and evaporated to dryness. Recrystallisation from methanol yields 5.1 g of N-(2-difluoromethoxyphenylsulfonyl)-N'-(4-ethyl-6-methoxy-1,3,5-triazin-2-yl)urea with a melting point of 114°-116° C.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)=[O:5].[OH2:17].[OH-].[Na+]>CO>[F:15][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:17])=[O:5])[CH:14]=[CH:13][CH:12]=1
Reactant: CON(C)C(=O)C1CC1c1cccc(F)c1
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1cccc(F)c1
Temperature: 25 °C

Procedure:
A mixture of 2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (8.96 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7.1 g).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[C:10]1([CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+].CC(O)=O>CO>[C:10]1([CH:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][N:1]2[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C1CCCN(CC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nipecotic acid (300 mg, 2.38 mmol), diphenylacetaldehyde (1.26 mL, 7.13 mmol), sodium cyanoborohydride (448 mg, 7.13 mmol), and HOAc (204 uL, 3.57 mmol) were dissolved in MeOH (20 mL) and stirred at ambient temperature overnight. The solution was concentrated under reduced pressure, take up in ether and 1N NaOH, extract with ether (3×), acidify the aqueous layer with 1N HCl, and extract with EtOAc (3×). The EtOAc layers were dried (MgSO4) and concentrated to give the title compound without further purification.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>>[Cl:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccc(Oc2ccccc2)cc1
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 33.4 %

Procedure:
Chlorosulfonic acid (9.7 mL, 0.147 mole) was added dropwise to 4-chlorophenoxybenzene (12.6 mL, 73.4 mmole) at room temperature with stirring. When addition was complete, the mixture was stirred at room temperature for 1 hour and then poured into ice water. The solid was collected by filtration, dried in the air, and recrystallized from petroleum ether and ethyl acetate to give 4-(4-chlorophenoxy)benzenesulfonylchloride (7.43 grams, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(OC([N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH:45]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:43]=[N:42]2)[CH2:37][CH2:36]1)=O)(C)(C)C>>[F:27][C:14]1[C:13]([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:43]=[N:42][N:41]([CH:38]5[CH2:39][CH2:40][NH:35][CH2:36][CH2:37]5)[CH:45]=4)[CH:3]=3)[NH:8][CH:9]=2)=[O:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(C5CCNCC5)c4)cc23)c1F

Procedure:
Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide P-1002 is prepared in two steps from propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide 9 and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester 34 as shown in Scheme 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:21])[C:7](=[O:20])[NH:8][N:9]=1.[H-].[Na+].Cl[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:17])([F:18])[F:19])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:21])[C:7](=[O:20])[N:8]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:9]=1
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a 0° C. solution of 6-bromo-4-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.364 g, 1.0 mmol) in THF (50 mL) was added sodium hydride (60% in mineral oil, 0.080 g, 2 mmol) and the reaction mixture was stirred for 0.5 h. (2-(chloromethoxy)ethyl)trimethylsilane (0.250 g, 1.5 mmol) was added and the mixture was stirred at ambient temperature for 2 h. The reaction was quenched with water (100 mL) and the aqueous mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3-20% EtOAc in petroleum ether) to give 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a white solid (0.330 g, 67%). 1H NMR (CDCl3, 400 MHz): δ 7.32 (s, 1H), 7.16 (s, 1H), 5.11 (q, J=8.8 Hz, 2H), 4.75 (d, J=12.6 Hz, 1H), 4.69 (q, J=6.4 Hz, 1H), 4.57 (d, J=12.6 Hz, 1H), 3.65 (t, J=8.4 Hz, 2H), 1.51 (d, J=6.8 Hz, 3H), 0.99 (t, J=8.4 Hz, 2H), 0.01 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26](=[O:29])[NH:27][CH3:28])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[C:31]1([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:25]([C:26]([NH:27][CH3:28])=[O:29])=[C:11]3[CH:12]=[C:13]([C:16]4[CH:24]=[CH:23][CH:22]=[C:18]([C:19](=[O:20])[NH:40][C:37]5([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH2:39][CH2:38]5)[CH:17]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC1(c2ccccc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12

Procedure:
2-(4-fluorophenyl)-N-methyl-5-(3-(1-phenylcyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide was prepared from 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.070 g, 0.14 mmol) and 1-phenylcyclopropanamine hydrochloride (0.040 g, 0.20 mmol). 1H NMR (500 MHz, DMSO-D6) δ ppm 9.40 (s, 1H), 8.90 (d, J=7.32 Hz, 1H), 8.35 (s, 1H), 8.11 (d, J=1.22 Hz, 1H), 8.03 (d, J=7.93 Hz, 1H), 7.98 (d, J=7.63 Hz, 2H), 7.90 (dd, J=8.70, 5.65 Hz, 2H), 7.65 (t, J=7.78 Hz, 1H), 7.49 (dd, J=7.32, 1.83 Hz, 1H), 7.28-7.35 (m, 4H), 7.23-7.26 (m, 2H), 7.15-7.20 (m, 1H), 2.81 (d, J=4.58 Hz, 3H), 1.32 (d, J=9.16 Hz, 4H). LCMS: retention time: 3.053 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 505 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([OH:25])=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:26][O:27][C:28](=[O:39])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:25][C:20]2[C:19]([C:9]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]4[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=4[N:10]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)COc1ccc(CBr)cc1
Reactant: Oc1ncccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Product: COC(=O)COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 3-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-pyridin-2-ol and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Brown solid (65%). MS (Turbo Spray): m/z=516.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:5].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:22][CH:21]=[CH2:20])=[CH:8][CH:7]=1)[CH3:5]
Reactant: C=CCBr
Reactant: COC(=O)C(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C(C)C(=O)OC)cc1
Temperature: 80 °C

Procedure:
A solution of the product of Example 46A (2.6 g, 12 mmol) in anhydrous dimethylformamide (20 mL) was treated with potassium carbonate (3.3 g, 24 mmol) and allyl bromide (1.2 mL, 13 mmol), and reaction heated for 16 hours at 80° C. Reaction mixture cooled and diluted with ethyl acetate. Mixture washed with water and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Residue purified by normal phase HPLC on silica gel eluting with 3% ethyl acetate/hexane to provide the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]1[CH3:18])(=[O:3])[CH3:2].[N+:19]([O-])([O-:21])=[O:20].[Na+]>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:19]([O-:21])=[O:20])=[CH:10][CH:11]=2)[CH:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: COC(=O)CC1c2ccccc2N(C(C)=O)C1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)CC1c2cc([N+](=O)[O-])ccc2N(C(C)=O)C1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 1-acetyl-2-methylindolin-3-ylacetate (6.83 g.) in concentrated sulphuric acid (45 ml.) was cooled to 0° C. and a solution of sodium nitrate (2.67 g.) in concentrated sulphuric acid (20 ml.) was added dropwise during 0.5 hr. The mixture was stirred at 0° C. for a further 0.5 hr. and then poured onto ice (300 ml.). The resulting precipitate was filtered and washed well with water. Crystallisation from methanol gave methyl 1-acetyl-2-methyl-5-nitroindolin-3-ylacetate, m.p. 106° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][C:12]2[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[N:6][CH:7]=1.BrC1C(C2C=CC(Cl)=CC=2)=CC2N(C(CC3C=NC(C(F)(F)F)=CC=3)=NN=2)C=1>C(O)(=O)C.FC(C1C=CC=CC=1)(F)F>[Br:1][C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]2[N:6]([C:10]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:8]=2)[CH:7]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CC(=O)NNc1cc(-c2ccc(Cl)cc2)c(Br)cn1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(Br)cn23)cn1
Solvent: CC(=O)O
Solvent: FC(F)(F)c1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Yield: 63.3 %

Procedure:
The title compound (61 mg, 60%) as a white powder was prepared from N′-(5-bromo-4-(4-chlorophenyl)pyridin-2-yl)-2-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)acetohydrazide (100 mg, 0.20 mmol) in glacial acetic acid (0.6 mL) and (trifluoromethyl)benzene (1.8 mL) by the procedures analogous to those described for 6-bromo-7-(4-chlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56D). LC/MS (method B): retention time=1.83 min, [M+H]+=481.0.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>CN(C=O)C.C(#N)C.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>[CH2:15]([C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH:14]=[CH2:13]
Reactant: COC(=O)c1ccc(C)cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=CCc1cc(C)ccc1C(=O)OC
Temperature: 90 °C
Yield: 79.5 %

Procedure:
A mixture of methyl 2-bromo-4-methylbenzoate (500 mg, 2.183 mmol), allyltributylstannane (0.744 mL, 2.401 mmol), lithium chloride (185 mg, 4.37 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (77 mg, 0.109 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90° C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution, dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4-methylbenzoate (330 mg, 1.735 mmol, 79% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.95-7.77 (m, 1H), 7.21-6.99 (m, 2H), 6.19-5.85 (m, 1H), 5.22-4.91 (m, 2H), 3.89 (s, 3H), 3.76 (d, J=6.6 Hz, 2H), 2.39 (s, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[OH:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:38]([O:42][CH3:43])(=[O:41])[CH:39]=[CH2:40].CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:40]=[CH:39][C:38]([O:42][CH3:43])=[O:41])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=1
Reactant: C=CC(=O)OC
Reactant: Oc1nc(-c2cccnc2)nc2ccc(I)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc2nc(-c3cccnc3)nc(O)c2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 6-iodo-2-(pyridin-3-yl) quinazolin-4-ol (synthesized as described in Scheme 1 and 4, substituting 5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (3.00 g, 8.6 mmol, 1.0 eq.), Pd(OAc)2 (48 mg, 0.21 mmol, 0.025 eq.) and PPh3 (113 mg, 0.43 mmol, 0.05 eq.) in DMF (8 mL) was added methyl acrylate (3.22 g, 25.8 mmol, 3.0 eq.) and DIPEA (1.22 g, 9.46 mmol, 1.1 eq.) under Ar atmosphere. The mixture was stirred at 110° C. overnight. After cooling, the mixture was filtered and the solid was washed with ethyl acetate three times to afford 1.30 g of xxxvi-a as green solid (yield 49%). LCMS m/z=308.0 (M+1) (Method B) (retention time=1.41 min).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[NH:27]1[C@H:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:30][C@@H:29]2[CH2:42][CH2:43][CH2:44][C@H:28]12>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:27]2[C@H:31]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:30][C@@H:29]3[CH2:42][CH2:43][CH2:44][C@H:28]23)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Reactant: O=C(O)CCCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4.92 g (30 mmol) of 4-phenylbutyric acid are dissolved together with 8.4 ml of triethylamine in 200 ml of dry tetrahydrofuran. While cooling in ice, 2.9 ml of ethyl chloroformate are added dropwise. After stirring at 0° C. for 1 hour, 7.4 g of benzyl (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride are added, and the mixture is stirred at room temperature for a further 12 hours. Filtration is followed by concentration, and the residue is taken up in 3% NaHCO3 /ethyl acetate. The organic phase is separated off and washed with 10% strength citric acid, 3% strength NaHCO3 solution and saturated brine, once each, dried with MgSO4 and concentrated. Chromatography on silica gel with ethyl acetate/cyclohexane (1:2) as mobile phase results in 9.05 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[N:19]([CH3:20])[NH:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].[ClH:29]>C(Cl)(Cl)Cl.N#N.CCOCC>[ClH:29].[CH2:22]([NH:26][C:27]([N:18]1[C:17](=[O:21])[CH2:16][CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[N:19]1[CH3:20])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: COc1ccc(C2CC(=O)NN2C)cc1OC1CCCC1
Reactant: CCCCN=C=O
Agent: Cl
Agent: N#N
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCCCNC(=O)N1C(=O)CC(c2ccc(OC)c(OC3CCCC3)c2)N1C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (2.06 mmol, 0.600 g) is dissolved in dry chloroform (10 mL) in a N2 atmosphere. To this is added dropwise at room temperature butyl isocyanate (5.15 mmol; 0.583 mL) neat. The sample is heated to reflux for 4 hours at which time TLC shows no starting material. The sample is evaporated to yield a clear oil which is dissolved in ether. To this solution is added ethanolic HCl and the sample is stirred for 15 minutes and evaporated in vacuo to afford a solid which is recrystallized from chloroform and hexane to give the title compound as a white solid (0.495 mg; 56%) m.p.: 115°-122° C. (dec) 1H NMR (DMSO-d6, 400 MHz) δ8.3 (s, 1H); 7.91 (t, 3H, J=5.7 Hz); 6.95 (d, 1H, J=1.3 Hz); 6.89 (d, 1H, J=8.3 Hz); 6.81 (dd, 1H, J=8.3, 1.6 Hz); 4.68 (m, 1H); 4.35 (d, 1H, J=5.6 Hz); 3.69 (s, 3H); 3.15 (m, 2H); 2.73 (s, 3H); 1.84 (m, 2H); 1.68 (m, 3H); 1.54 (m, 2H); 1.40 (m, 2H); 1.23 (m, 3H); 0.85 (t, 2H, J=7.3 Hz). IR (KBr, cm-1) 1760