Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH2:32][C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH2:32][C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)=[O:29]
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Reactant: NCc1nc2ccccc2[nH]1
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3c(OC)ccc(OC)c3CCN2CC(=O)NCc2nc3ccccc3[nH]2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-(aminomethyl)-benzimidazole
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][CH2:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.C(=O)([O-])O.[K+]>ClC=CCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:13]1[CH:29]=[CH:28][C:16]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)=[O:38]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)c1ccc(CCc2ccc(SCc3ccc4ccccc4n3)cc2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC=CCl
Product: O=C(O)c1ccc(CCc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1

Procedure:
4-(4-(2-quinolinylmethylthio)phenethyl)benzoic acid (4 mmol) in dichloroethene (50 ml) is stirred with m-chloroperbenzoic acid (4 mmol) and solid potassium hydrogen carbonate (1.0 g). The reaction is assayed byTLC and upon consumption of the starting thio compound, the mixture is filtered, washed with dilute aqueous sodium bisulfite, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfinyl)phenethyl)benzoic acid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[S-:15][C:16]#[N:17].[NH4+].[C:19]([C:22]1[CH:30]=[CH:29][C:25]([NH:26][CH2:27][CH3:28])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>CC(C)=O.CN(C=O)C>[CH2:27]([N:26]([C:16]1[S:15][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[N:17]=1)[C:25]1[CH:29]=[CH:30][C:22]([C:19](=[O:21])[CH3:20])=[CH:23][CH:24]=1)[CH3:28]
Reactant: CCNc1ccc(C(C)=O)cc1
Reactant: O=C(O)c1cccnc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: CCN(c1ccc(C(C)=O)cc1)c1nc(=O)c2cccnc2s1
Yield: 83.9 %

Procedure:
The reaction procedure of Example 85 was followed except that 1.576 g (10 mmol) of 2-chloronicotinic acid, 10 ml of thionyl chloride, two droplets of DMF, 837 mg of ammonium thiocyanate, 10 ml of acetone, 3.986 g of 4-acetyl-N-ethylaniline and 10 ml of acetone were used. The resulting crude product was then recrystallized from ethanol to obtain 2.729 g of 2-[N-ethyl-N-(4-acetylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=C(C#N)[CH:16]=[CH:15][N:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:21].[Na+].Cl.[CH3:24][CH2:25][OH:26]>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[C:24]([CH:16]=[CH:15][N:14]=3)[C:25]([OH:21])=[O:26])[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2ccnn2-c2cc(C(=O)O)ccn2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 2-[5-(4-methylphenyl)-1H-pyrazol-1-yl]pyridine-4-carbonitrile (120 mg, 0.46 mmol) in EtOH (1 mL) was added 10 M NaOH (1 mL) at rt, then stirred at 90° C. for 1 h. The reaction mixture was cooled, acidified with 1 N HCl to pH=3, extracted with EtOAc (20 mL), and washed with water and brine. The organic phase was dried, concentrated, triturated with EA/PE (1:1, 5 mL), filtered, and dried to give the title compound (60 mg, 47%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 2.30 (3H, s), 6.65 (1H, d, J=2.0 Hz), 7.13 (4H, s), 7.77 (1H, dd, J=4.8, 1.2 Hz), 7.82 (1H, d, J=1.2 Hz), 8.44 (1H, d, J=4.8 Hz), 13.97 (1H, br s). [M+H] Calc'd for C16H13N3O2, 280. Found, 280.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([OH:18])[C:14]=3[CH:19]=2)=[CH:6][CH:5]=1.Br[CH2:23][C:24]1([CH3:28])[CH2:27][O:26][CH2:25]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1C2C=CC=CC=2C=N1>CN(C=O)C.C(OCC)(=O)C>[CH3:23][C:24]1([CH2:28][O:18][C:15]2[C:14]3[CH:19]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:5][CH:6]=4)[CH:11]=[CH:12][C:13]=3[O:17][N:16]=2)[CH2:27][O:26][CH2:25]1
Reactant: CC1(CBr)COC1
Reactant: Oc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc2oncc2c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(COc2noc3ccc(-c4ccc(OC(F)(F)F)cc4)cc23)COC1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-ol (100 mg, 0.34 mmol), 3-bromomethyl-3-methyloxetane (150 mg, 0.91 mmol) and cesium carbonate (300 mg) were combined in 5 mL DMF and stirred at ambient temperature until HPLC showed complete disappearance of benzisoxazole starting material. The reaction mixture was diluted with 60 mL ethyl acetate, washed with water and brine and evaporated under vacuum. Flash chromatographic purification on 12 g silica gel with 0-60% ethyl acetate in hexane gave the title compound (80 mg, 0.21 mmol).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[N:23](C)S(N)(=O)=O.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.CC(N(C)C)=O>[CH:1]1[C:11]2[C:10]3=[CH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH2:23])=[O:21])=[CH:17][C:18]=4[N:9]3[CH2:8][CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Reactant: CN(C)S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: NC(=O)c1ccc2cc3n(c2c1)CC=Cc1ccccc1-3
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[[4-(4-morpholinylcarbonyl)-1-piperazinyl]carbonyl] (70 mg, 0.12 mmol), N,N-dimethylsulfamide (75 mg, 0.60 mmol) and DMAP (75 mg, 0.61 mmol) in dimethylacetamide (1.5 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol). The reaction solution was stirred at 50° C. overnight, concentrated, purified by preparative HPLC (MeOH/2O with NH4OAc buffer) and repurified by preparative HPLC (MeOH/2O with TFA buffer) to yield 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[[4-(4-morpholinylcarbonyl)-1-piperazinyl]carbonyl] (28 mg, 0.041 mol, 34%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 9.09 (br s, 1H), 8.11 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.58 (br d, J=7.3 Hz, 1H), 7.54-7.45 (m, 3H), 7.41 (br d, J=7.3 Hz, 1H), 6.87 (s, 1H), 5.16 (br s, 1H), 4.37 (br s, 1H), 3.66 (dd, J=4.6, 4.6 Hz, 4H), 3.59-3.40 (m, 4H), 3.27(dd, J=4.6, 4.6 Hz, 4H), 3.19-3.07 (m, 4H), 3.06 (s, 6H), 2.89-2.80 (m, 1H), 2.13-1.17 (m, 10H). LCMS: m/e 674 (M−H)−, ret time 1.85 min, column A, 2 minute gradient.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:36]5[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]5)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: N#CC1CNC1
Agent: Cl
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CC(C#N)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and azetidine-3-carbonitrile hydrochloride (Astatech, Cat. No. 52028). LCMS (M+H)+: m/z=524.3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([OH:3])=O.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:44]([S:49]([NH2:52])(=[O:51])=[O:50])[CH2:45][CH2:46][CH2:47][CH3:48]>O>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH2:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1](=[O:3])[NH:52][S:49]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])(=[O:51])=[O:50])[CH:5]=2)[NH:9][CH:8]=1
Reactant: CCCCCS(N)(=O)=O
Reactant: O=C(O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: O
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2[nH]cc(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
N,N′-Carbonyldiimidazole (0.282 g) is added to an N,N-dimethylfornamide (4.3 ml) solution of 5-carboxy-3-(2,4-dichlorobenzyl)indole (0.429 g), and stirred at room temperature for 1 hour. Diazabicycloundecene (0.306 g) and 1-pentanesulfonamide (0.304 g) are added thereto, and stirred at 100° C. for 40 hours. The reaction mixture is cooled, and then made acidic with water and 1M HCI added thereto. Then, the gummy residue formed is collected. This is dissolved in ethyl acetate, washed with water, and dried. The solvent is evaporated away, and the resulting residue is crystallized from ether. The crystal formed is collected and dried to obtain 3-(2,4-dichlorobenzyl)-5-(1-pentanesulfonylcarbamoyl)indole (88) (0.258 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.[CH3:22][C:23]([O:41][Si:42]([CH2:47][CH3:48])([CH2:45][CH3:46])[CH2:43][CH3:44])([CH3:40])[CH2:24][CH2:25][C:26]1[S:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:28]4[S:27][C:26]([CH2:25][CH2:24][C:23]([CH3:40])([O:41][Si:42]([CH2:47][CH3:48])([CH2:43][CH3:44])[CH2:45][CH3:46])[CH3:22])=[CH:30][CH:29]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CC[Si](CC)(CC)OC(C)(C)CCc1ccc(B2OC(C)(C)C(C)(C)O2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC[Si](CC)(CC)OC(C)(C)CCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)s1
Temperature: 150 °C

Procedure:
5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (90 mg, 0.24 mmol), ({1,1-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]propyl}oxy)(triethyl)silane (149 mg, 0.36 mmol, 1.5 eq), potassium carbonate (200 mg, 1.4 mmol, 6 eq), and palladium tetrakistriphenylphosphine (28 mg, 0.024 mmol, 0.1 eq) were diluted in dioxane (1.5 mL) and water (0.5 mL) in a 2-5 mL microwave vial. The mixture was degassed by bubbling argon through for 5 minutes, then heated in a microwave oven at 150° C. under high absorption for 40 minutes. The mixture was filtered through a thiol SPE cartridge, then concentrated to give the crude product as a brown oil. This material was purified by Isco Combiflash, 40 gram column, eluting with 0-15% methanol in dichloromethane. The desired product was obtained as a brownish tarry substance and was re-purified by ammonium hydroxide Gilson eluting with 20-95% acetonitrile in water. The product fractions were concentrated in a Genevac EZ2 evaporator to give the title compound as a light yellow solid (55 mg, 40%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([N:8]=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[NH2:25].[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[Na+]>C(O)(=O)C.O>[Cl:26]([O-:30])(=[O:29])(=[O:28])=[O:27].[NH2:24][C:21]1/[C:22](=[N:8]/[C:5]2[C:4](=[O:10])[N:3]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])/[CH:23]=[C:18]([CH3:17])[C:19](=[NH2+:25])[CH:20]=1
Reactant: Cc1c(N=O)c(=O)n(-c2ccccc2)n1C
Reactant: Cc1ccc(N)cc1N
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: CC1=C/C(=N\c2c(C)n(C)n(-c3ccccc3)c2=O)C(N)=CC1=[NH2+]
Reaction time: 0.5 h

Procedure:
50 mmol of 1,5-dimethyl-4-nitroso-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in a solution of 850 ml of acetic acid and 1250 ml of water. This solution was admixed with 50 mmol of 4-methylbenzene-1,3-diamine and stirring was continued for 2 h 30 min. Sodium perchlorate was added to saturation, and the mixture was left to stand for 30 minutes at zero degrees.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2)[CH2:15][CH3:16].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([F:34])[CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH:14]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH2:15][CH3:16])[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
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
Solvent: CCOC(C)=O
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1cc(F)cc(F)c1
Temperature: 100 °C

Procedure:
To a mixture of 3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one (from example 3, step 2; 0.030 g, 0.065 mmol) and (3,5-difluorophenyl)boronic acid (Aldrich, 12.3 mg, 0.0780 mmol) in 1,4-dioxane (0.5 mL) was added a 1M solution of sodium carbonate (8.27 mg, 0.0780 mmol) in water (0.077 mL) and tetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on RP-HPLC at pH 10 conditions (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the desired product. LCMS calculated for C23H20F2N7O (M+H)+: m/z=448.2. Found: 448.3. 1H NMR (DMSO-d6, 300 MHz) δ 8.06 (2H, m), 7.61 (1H, m), 7.38 (1H, m), 7.14 (5H, m), 6.88 (1H, m), 5.08 (1H, m), 2.83 (3H, s), 1.75 (2H, m), 0.70 ((3H, t, J=7.8 Hz) ppm. 19F NMR (DMSO-d6, 282 MHz) δ −111 ppm.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[C:18]([OH:20])=O.C(N(CC)CC)C.C1(NP(Cl)(=O)OC2C=CC=CC=2)C=CC=CC=1.[CH2:50]([NH2:54])[CH:51]([CH3:53])[CH3:52]>ClCCl>[CH2:50]([NH:54][C:18](=[O:20])/[CH:17]=[CH:16]/[CH:15]=[CH:14]/[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][C:5]1[CH:21]=[CH:22][CH:23]=[C:3]([C:2]([F:1])([F:25])[F:24])[CH:4]=1)[CH:51]([CH3:53])[CH3:52]
Reactant: CC(C)CN
Reactant: O=C(O)/C=C/C=C/CCCCCCOCc1cccc(C(F)(F)F)c1
Agent: O=P(Cl)(Nc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CNC(=O)/C=C/C=C/CCCCCCOCc1cccc(C(F)(F)F)c1
Yield: 49.5 %

Procedure:
The product of step (d) (1 g, 2.8 mmol) was treated with triethylamine (0.66 mL, 4.8 mmol) and phenyl N-phenylphosphoroamidochloridate (1 g, 3.8 mmol) in dry dichloromethane for 30 mins under nitrogen at room temperature. Isobutylamine (0.66 mL, 6.6 mmol) and triethylamine (0.66 mL, 4.8 mmol) were added and after 24 hours the reaction mixture was subjected to standard work-up procedures. The crude product was purified by column chromatography (1:1 hexane:ether, silica) to give 0.57 g (50% of theory) of N-isobutyl 11-(3'trifluoromethylbenzyloxy)-(2E,4E)-undecadienamide. mp 48°-50°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[H][H]>[Pt].[Pt]=O.C(OC(=O)C)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: Brc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc2[nH]cc(C3CCNCC3)c2c1
Reaction time: 18 h
Yield: 75.5 %

Procedure:
To a solution of 13.61 gm (49 mmol) 5-bromo 3-[1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole in 75 ml 2:1 tetrahydro-furan ethyl acetate were added 8.0 gm 3% sulfided platinum on carbon and 4.0 gm platinum oxide. The reaction mixture was hydrogenated with an initial hydrogen pressure of 60 p.s.i. at 40° C. for 18 hours and then at ambient temperature for 30 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 10.33 gm (75.6%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][Cl:39])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][Cl:39])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 94.9 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-mercapto-phenyl)-urea (319 mg, 1.098 mmol) described in Example 44A in THF: DMF (2:1, 6 mL) was added NaH (95%, 30.5 mg, 1.207 mmol), stirred for 5-10 min at ambient temperature. Then 4-chloro-7-(2-chloro-ethoxy)-6-methoxy-quinazoline from Example 35A (300 mg, 1.098 mmol) was added as a solution in DMF:THF (2:1). The reaction mixture was then stirred overnight. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and washed the ethyl acetate layer with water and brine successively. The organic layer was dried (Na2SO4) concentrated to dryness to get the pure compound 1-(5-tert-Butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (550 mg, 95%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.55-7.25 (m, 5H), 6.45 (s, 1H), 4.50 (m, 2H), 4.05 (m, 5H), 1.25 (s, 9H); LC-MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]3[CH2:28][O:27]3)[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][CH:26]([OH:27])[CH2:28][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[N:9]=2)[CH:7]=1
Reactant: O=C(Nc1cn(CC2CO2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cn(CC(O)CN2CCOCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(oxiran-2-ylmethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL), DIEA (67 mg, 0.518 mmol) and morpholine (14 mg, 0.161 mmol) was added at room temperature. The resulting solution was stirred at 60° C. overnight, cooled, diluted with 30 mL of ethyl acetate, washed with 2×10 mL of water and 2×10 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with dichloromethane/methanol (95/5). This resulted in 50 mg of crude product, which was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A: Water/0.05% NH4HCO3, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min; 254 nm to obtain 40 mg (67%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-hydroxy-3-(morpholin-4-yl)propyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. LCMS (Method 35) [M+H]+=548.2, RT=2.28 min. 1H-NMR (300 MHz, DMSO-d6): δ (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 7.2 Hz), 8.68-8.67 (m, 2H), 8.34 (s, 1H), 7.65 (d, 1H, J=2.7 Hz), 7.61 (s, 1H), 7.44 (d, 1H, J=8.7 Hz), 7.27 (dd, 1H, J=4.2, 6.9 Hz), 7.00 (t, 1H, J=73.5 Hz), 4.99 (d, 1H, J=4.5 Hz), 4.31-4.28 (m, 1H), 4.13-4.07 (m, 2H), 3.56 (t, 4H, J=4.5 Hz), 2.42 (t, 4H, J=4.5 Hz), 2.32 (d, 2H, J=4.8 Hz).
Reaction SMILES: C(=O)([O-])OC(C)(C)C[CH:5]([C:15]1C=C[C:18]([C:21]#[C:22][C:23]2[C:28]([N:29](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:27][CH:26]=[C:25]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:52])=[O:51])=[CH:46][CH:45]=3)[N:24]=2)=[CH:17][CH:16]=1)[CH2:6][NH:7]C(OC(C)(C)C)=O.[C:60](O)([C:62](F)(F)F)=O.CC[O:69]CC>C(Cl)Cl>[NH2:7][CH2:6][CH:5]([C:15]1[CH:62]=[CH:60][C:18]([C:21]#[C:22][C:23]2[C:28]([NH2:29])=[N:27][CH:26]=[C:25]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:52])=[O:51])=[CH:46][CH:45]=3)[N:24]=2)=[CH:17][CH:16]=1)[OH:69]
Reactant: CCOCC
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C#Cc3ccc(C(CNC(=O)OC(C)(C)C)CC(C)(C)OC(=O)[O-])cc3)n2)cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C#Cc3ccc(C(O)CN)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a solution of [1-[4-[2-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]ethynyl]phenyl]-2-(tert-butoxycarbonylamino)ethyl]tert-butyl carbonate (250.3 mg, 0.2990 mmol) in DCM (2.503 mL) was added TFA (1 mL, 12.98 mmol) and the mixture was stirred at ambient temperature for 18 hours. After this time ether was added to the reaction mixture, the precipitate which resulted was isolated by filtration and dried under vacuum. The filtrate was recombined with precipitate and re-dissolved in DCM. Polymer supported 3-Mercaptopropyl ethyl sulfide was added to the solution and this was left to stir for 15 minutes at ambient temperature. After this time the resin was removed by filtration and washed with DCM. The filtrate was concentrated in vacuo and the material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge to give the titled product as a solid (15.01 mg, 11.5% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.18 (d, J=6.8 Hz, 6H), 2.65 (dd, J=8.1, 12.8 Hz, 2H), 3.45 (t, J=6.8 Hz, 1H), 4.58 (dd, J=3.7, 7.9 Hz, 1H), 5.60 (br s, 1H), 7.15 (s, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.5 Hz, 2H), 8.24 (d, J=8.5 Hz, 2H) and 8.75 (s, 1H) ppm; MS (ES+) 437.1.