Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35](O)=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35]([NH:44][S:41]([CH:38]4[CH2:40][CH2:39]4)(=[O:43])=[O:42])=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 64.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(3,4-difluorophenyl)piperidine-1-carbonyl]-7-(2,5-dimethylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.20 mmol) obtained in Example 88, step 4 and cyclopropanesulfonamide (121 mg, 1.0 mmol), the title compound (79 mg, 65%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[F:21])=[N:8][CH:7]=[N:6]2.CO.[Cl-].[NH4+]>C1COCC1.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[F:21])=[N:8][CH:7]=[N:6]2
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 5-chloro-4-(2-fluoro-4-nitrophenoxy)pyrrolo[2,1-f][1,2,4]triazine (2.00 g, 6.48 mmol) in THF (50 mL)/MeOH (80 mL) was added zinc dust (2.12 g, 32.4 mmol) followed by ammonium chloride (1.73 g, 32.4 mmol). After stirring at rt for 8 h, the reaction mixture was filtered through Celite® with MeOH and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with water (2×100 mL) then brine (1×100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50 % EtOAc/hexanes) to give the title compound (1.51 g, 84%) as a pale yellow solid. 1H NMR (CDCl3) δ 7.95 (s, 1H), 7.69 (d, 1H, J=2.8 Hz), 7.09 (t, 1H, J=8.4 Hz), 6.79 (d, 1H, J=2.8 Hz), 6.58 (dd, 1H, J=11.6, 2.6 Hz), 6.51 (d, 1H, J=8.7 Hz), 3.92 (br s, 2H); MS(ESI+) m/z 279.2 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)(C(C)(C)C)(C)C.[H-].[Na+].I[CH3:24]>CN(C=O)C>[Cl:20][C:15]1[N:14]=[C:13]([N:12]([CH3:24])[CH2:11][CH2:10][CH2:9][OH:8])[C:18]([CH3:19])=[CH:17][N:16]=1
Reactant: CI
Reactant: Cc1cnc(Cl)nc1NCCCO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1N(C)CCCO
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a solution of N-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-2-chloro-5-methyl-4-pyrimidinamine (Example 340, 5.00 g, 15.8 mmol) in DMF (60 mL) was added portionwise NaH (0.95 g, 60% dispersion in mineral oil, 23.7 mmol) [H2 evolution]. The heterogeneous mixture was stirred for 30 min, then iodomethane (1.97 mL, 31.7 mmol) was added. After 3 h of stirring at rt, the excess NaH was quenched by the slow addition of a saturated solution of NH4Cl [H2 evolution]. The product was extracted with Et2O. The combined organic layers were then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using a pad of silica gel (3:1 hexanes/EtOAc) and the desired fractions were concentrated under reduced pressure. The resulting silyl derivative was dissolved in a mixture of ethanol (46 mL) and HCl (4.2 mL of a 2 N aqueous solution), and stirred at rt until the reaction was complete (6-10 h). The reaction mixture was then concentrated under reduced pressure, diluted with EtOAc, and washed with a saturated solution of NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexanes/EtOAc) to yield the title compound (1.22 g, 62%). 1H NMR (400 MHz, CDCl3) δ 1.83 (qt, 2H), 2.32 (s, 3H), 3.19 (s, 3H), 3.56 (t, 2H), 3.69 (t, 2H), 7.70 (s, 1H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:24][C:23]1=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([S:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:6])[NH:24][C:23]1=[O:33])[CH3:21])([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1Sc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1S(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.7 %

Procedure:
1.5 g of 3-chloroperoxybenzoic acid was added, whilst ice-cooling, to a solution of 2 g of (3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-phenylthio-2-azetidinone [prepared as described in step (i) above] in 30 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 6 hours. At the end of this time, the reaction mixture was mixed with 30 ml of methylene chloride, and the organic layer was separated and washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and again with water, in that order. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash chromatography, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent, to give 1.9 g of the title compound consisting of two diastereomers, differing in the configuration of the sulfoxide group, as colorless crystals, melting at 65°-70° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:24][CH3:25])[CH:10]=2)[N:5]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].ClCCl>O>[CH2:28]([N:30]([CH2:2][CH2:3][C:4]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:11]2[C:6](=[CH:7][C:8]([O:26][CH3:27])=[C:9]([O:24][CH3:25])[CH:10]=2)[N:5]=1)[CH2:31][CH3:32])[CH3:29]
Reactant: COc1ccc(-c2nc(CCBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: CCNCC
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCc1nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2n1
Yield: 8.4 %

Procedure:
A mixture of 2-(2-bromoethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.486 g), diethylamine (0.41 g) and dichloromethane (10 ml) was stirred under reflux for 6 hours. The reaction mixture was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform - ethyl acetate (1:1, v/v) gave 2-[2-(N,N-diethylamino)ethyl]-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinazoline (0.040 g, 8%). This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 164°-166° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(C(C)=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
28.87 g (187.5 mM) of 2-nitro-4-hydroxyaniline in 600 ml of methyl ethyl ketone (MEK) are treated with 77.6 g of potassium carbonate and 22.3 ml (187.5 mM) of benzyl bromide. The reaction mixture is heated at reflux for3 h and is then evaporated to dryness. The evaporation residue is triturated in hexane, is filtered and dried under vacuum. There are thus isolated 40 g (88.9%) of the expected derivative, of melting point 106° C.
Reaction SMILES: I[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[CH3:24][NH:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.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>[CH3:24][NH:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:2]3[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]=[C:7]4[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH:32]=2)[N:27]=1
Reactant: Cc1ccc2c(Oc3cccc(C(F)(F)F)c3)nccc2c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1ncc2cc(-c3c(C)ccc4c(Oc5cccc(C(F)(F)F)c5)nccc34)ccc2n1
Temperature: 150 °C

Procedure:
5-Iodo-6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinoline (0.170 g, 0.396 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.124 g, 0.436 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (0.0139 g, 0.0198 mmol), and sodium carbonate (0.0840 g, 0.792 mmol) were all placed in a clear microwave vial along with 5 ml of 9:1 DMF:water. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with water and extracted with EtAOc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30-70% EtOAc in hexanes. The clean fractions were reduced in vacuo and the residue triturated with ether to give N-methyl-6-(6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-yl)quinazolin-2-amine as a light yellow solid. MS (M+H)+ 461.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:42][CH2:41][CH2:40][O:39][CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: COCCN
Product: COCCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methoxyethylamine according to conditions described in general procedure C. Mp: 87-88° C.;
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)([CH3:4])[CH3:3].Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][C:24]([CH3:30])([CH3:29])[CH2:23][C:22]2([CH3:32])[CH3:31]>>[CH3:29][C:24]1([CH3:30])[CH2:23][C:22]([CH3:32])([CH3:31])[C:21]2[C:26](=[CH:27][CH:28]=[C:19](/[C:5](/[Si:2]([CH3:3])([CH3:4])[CH3:1])=[CH:6]/[C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH:20]=2)[O:25]1
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Product: CCOC(=O)c1ccc(/C=C(/c2ccc3c(c2)C(C)(C)CC(C)(C)O3)[Si](C)(C)C)cc1

Procedure:
Following General Procedure A, ethyl 4-[(trimethylsilyl)ethynyl]benzoate (Compound 9, 0.51 g, 2.0 mmol) and 6-bromo-2,2,4,4-tetramethylchroman (0.57 g, 2.25 mmol) were coupled to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[CH:11][C:10]([CH:13]=O)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[CH3:16][O:17][NH2:18]>N1C=CC=CC=1>[CH3:16][O:17][N:18]=[CH:13][C:10]1[CH:11]=[CH:12][N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=1
Reactant: O=Cc1ccn(-c2ncccc2Cl)n1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1ccn(-c2ncccc2Cl)n1
Yield: 97.8 %

Procedure:
A mixture of 2.00 g of 1-(3-chloro-2-pyridinyl)-1H-pyrazole-3-carbaldehyde, 1.21 g of O-methylhydroxylamine hydrochloride and 8 ml of pyridine was heated to reflux for 1 hour. After the reaction mixture was concentrated under reduced pressure, an aqueous saturated sodium hydrogen carbonate solution was poured into the residue and the mixture was extracted with methyl t-butyl ether three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 2.23 g of 1-(3-chloro-2-pyridinyl)-1H-pyrazole-3-carbaldehyde O-methyloxime of the formula:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[CH:5]=[CH:4][C:3]=1[C:25](=[O:27])[CH3:26]>C(O)C.CN(C)C=O.[Pd]>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:5]=[CH:4][C:3]=1[C:25](=[O:27])[CH3:26]
Reactant: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(N)cc2)ccc(C(C)=O)c1O
Reaction time: 1.5 h

Procedure:
1-{2-Hydroxy-3-propyl-4-[3-(4-nitrophenoxy)propoxy]phenyl}ethanone (19.6 g) was dissolved in a mixture of ethanol (300 ml) and dimethylformamide (100 ml), to which was added under nitrogen, a slurry of palladium on charcoal catalyst (1.0 g, 5%) in ethanol (50 ml). The suspension was then hydrogenated on a Parr at 60 psi and room temperature for 90 minutes. The suspension was filtered over Celite (registered Trade Mark), washed with ethanol and the filtrate evaporated under reduced pressure to a brown oil, which was triturated with water and filtered to give a brown solid. The solid was recrystallised from ethanol with charcoal to give a white solid, m.p. 75°-77° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[CH:28]1([C:33]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:9][CH:8]=3)[CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)C1CNCC(c2ccc(C(C)C)cc2)C1
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(c2ccc(C(C)C)cc2)CN(C(=O)C2CCCC2)C1

Procedure:
1.5 g (5.3 mmol) of ethyl 5-[4-(1-methylethyl)phenyl]piperidine-3-carboxylate were dissolved in 18 ml of dichloromethane, and 0.81 g (7.9 mmol) of triethylamine was added at 0° C. 1.43 g (10.5 mmol) of cyclopentanecarbonyl chloride were then added dropwise.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12](=[S:14])[NH2:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3].Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12]2[S:14][CH:30]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3]
Reactant: CCOC(=O)C(=O)CBr
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Product: CCOC(=O)c1csc(N2N=C(c3cc(F)ccc3F)SC2(CCCN=[N+]=[N-])c2ccccc2)n1

Procedure:
Prepared from 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide as in Example 21, Step C, utilizing ethyl 3-bromo-2-oxopropanoate in place of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate, 57%.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[C:46]([F:48])[C:45]([OH:49])=[CH:44][CH:43]=2)=[C:38]([O:50][SiH:51]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:37]=1)([CH3:35])([CH3:34])[CH3:33].[CH2:64](O)[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71]>O1CCCC1>[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:47]=[C:46]([F:48])[C:45]([O:49][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:44][CH:43]=2)=[C:38]([O:50][SiH:51]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCCCCCO
Reactant: CC(C)(C)c1ccc(-c2ccc(O)c(F)n2)c(O[SiH](c2ccccc2)c2ccccc2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(C(C)(C)C)cc2O[SiH](c2ccccc2)c2ccccc2)nc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
2.30 g (13.35 mmol) of diethyl azodicarboxylate are added dropwise at 0° C. to 3.47 g (13.35 mmol) of triphenylphosphine in 100 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 minutes. 3.58 g (8.10 mmol) of 6-(4-tert.-butyldiphenylsilyloxyphenyl)-2-fluoro-3-hydroxypyridine and 1.70 g (13.35 mmol) of 1-octanol are then added. After a reaction time of 1.5 hours at room temperature, the solvent is distilled off, and the residue is purified by chromatography (silica gel, 95:5 hexane/ethyl acetate), giving 4.43 g of 6-(4-tert.-butyldiphenylsilyloxyphenyl)-2-fluoro-3-octyloxypyridine. ##STR46##
Reaction SMILES: [CH3:1][C:2]([CH:5]=O)([CH3:4])[CH3:3].[CH3:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13]>CO.C(O)(=O)C>[CH3:4][C:2]([CH3:1])([CH3:3])[CH:5]=[N:15][NH:14][C:12](=[O:13])[C:11]1[CH:16]=[CH:17][CH:18]=[C:9]([O:8][CH3:7])[C:10]=1[CH3:19]
Reactant: COc1cccc(C(=O)NN)c1C
Reactant: CC(C)(C)C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(C(=O)NN=CC(C)(C)C)c1C
Yield: 66.6 %

Procedure:
Pivaldehyde (13.45 g, 156 mmoles) was dissolved in 300 mL methanol in a round bottom flask. 3-methoxy-2-methyl-benzoic acid hydrazide (26.6 g, 147.6 mmoles) and 150 drops glacial acetic acid were added, and the mixture was heated at reflux for ca. 8 hours, while monitoring by TLC. Upon completion of the reaction, the solvent was removed in vacuo, and the product was slurried in cold hexanes and filtered on a Büchner funnel to provide 24.4 g (66%) of 3-methoxy-2-methyl-benzoic acid (2,2-dimethyl-propylidene)-hydrazide. Rf=0.19, (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, DMSO-d6) δ 7.42+7.41 (3 s, 1H), 7.1 (t, 1H), 6.9 (d, 1H), 6.82 (d, 1H), 3.78 (s, 3H), 2.2+2.1 (2 s, 3H), 1.07+1.0 (3 s, 9H), multiple conformations, possibly E/Z mixture.
Reaction SMILES: CO.C(O[C:6]([C:8]1[C:9]([NH:16][C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[N:22][NH:23]3)=[CH:19][CH:18]=2)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=1)=[O:7])C.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>O>[CH:26]1([NH:29][C:6]([C:8]2[C:9]([NH:16][C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[N:22][NH:23]4)=[CH:19][CH:18]=3)=[N:10][C:11]([S:14][CH3:15])=[N:12][CH:13]=2)=[O:7])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2cn[nH]c2c1
Reactant: NC1CC1
Solvent: CO
Solvent: O
Product: CSc1ncc(C(=O)NC2CC2)c(Nc2ccc3cn[nH]c3c2)n1
Yield: 65 %

Procedure:
To the solution of methanol (20 ml) was added 4-(1H-6-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (1g) prepared from preparation example 2, added cyclopropylamine (7 ml) at room temperature, and reacted at 50° C. for 6 hr. The reaction mixture was cooled, and stirred at 25° C. for 0.5 hr with slowly adding H2O (20 ml). The reaction mixture was filtered, washed with 30% aqueous methanol solution (10 ml), obtained the desired compound (0.67 g, 65%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[C:12]([CH3:27])([CH3:26])[CH2:11][CH2:10]1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:23]([C:22]2[CH:21]=[N:20][N:17]3[CH:18]=[CH:19][C:14]([N:13]4[C@@H:9]([C:3]5[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=5[F:1])[CH2:10][CH2:11][C:12]4([CH3:27])[CH3:26])=[N:15][C:16]=23)=[O:25])[CH2:30][CH2:29]1
Reactant: NC1CC1
Reactant: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(=O)O)c2n1
Product: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(=O)NC3CC3)c2n1
Yield: 39 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and cyclopropylamine in Step D. The crude material was purified by reverse phase HPLC (0-75% acetonitrile/water) to provide the title compound (11 mg, 39% yield). MS (apci) m/z=412.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O1CCOCC1.O>[CH3:32][C@H:30]1[O:29][C@H:28]([CH3:33])[CH2:27][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:39]4[CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][CH:23]=2)[CH2:31]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@@H](C)O1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a solution of 6-chloro-4-(5-{[(2R,6R)-2,6-dimethyl-4-morpholinyl]methyl}-1,3-oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (109.5 mg, 0.225 mmol), N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methanesulfonamide (148 mg, 0.450 mmol) and sodium bicarbonate (56.7 mg, 0.675 mmol) in 1,4-Dioxane (5 mL) and Water (1.5 mL) stirred in air at room temp was added solid Solvias Catalyst (12.60 mg, 0.022 mmol). The reaction mixture was stirred at 120° C. for 2 hr. After this time, sodium hydroxide solution (2N, 0.5 mL) was added and the reaction mixture left to stir at room temperature for two hours. On cooling, the reaction mixture was passed through a celite cartridge (10 g) and washed with ethyl acetate. The resulting solution was evaporated and the crude residue purified by MDAP (Method C). Appropriate fractions were combined and concentrated in vacuo to afford the title compound (43 mg).