Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-chloro-4-fluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.22 (s, 1H), 7.26 (t, J=9.1 Hz, 1H), 7.09 (dd, J=8.7, 2.3 Hz, 1H), 7.03 (m, 2H), 6.91 (m, 1H), 6.88 (d, J=2.3 Hz, 1H), 3.26 (s, 3H), 1.97 (m, 4H), 0.82 (t, J=7.2 Hz, 6H); MS (ESI) m/z 363/365 ([M+H]+); MS (ESI) m/z 361/363 ([M−H]−); Anal. calcd for C19H20ClFN2O2: C, 62.90H, 5.56; N, 7.72. Found: C, 62.65; H, 5.53; N, 7.58.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][N:3]=1
Reactant: Cc1nc(Cl)ncc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cnc(Cl)nc1C
Yield: 86.8 %

Procedure:
A solution of 2-chloro-4-methylpyrimidin-5-amine (10 g, 68.26 mmol, 1.00 equiv, 98%) and acetic anhydride (14.3 g, 137.27 mmol, 2.01 equiv, 98%) in acetic acid (50 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum to give 11 g (82%) of N-(2-chloro-4-methylpyrimidin-5-yl)acetamide as an off-white solid
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>>[CH2:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:12])[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: O=c1ccc2ccc(Br)cc2[nH]1
Product: CCOC(=O)CCn1c(=O)ccc2ccc(Br)cc21
Yield: 94 %

Procedure:
The compound was obtained according to procedure H starting from 7-bromoquinolin-2(1H)-one (commercial; 561 mg, 2.5 mmol) and ethyl acrylate (0.27 mL, 2.5 mmol, 1 eq.). The crude orange oil (0.76 g; 94% yield) was used as such in the next step.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[F:29][C:28]([F:30])([F:31])[C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)[CH:14]=1)=[O:32]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1ccc(CCl)cc1
Yield: 94 %

Procedure:
Using an analogous procedure to that described in Example 37, 4-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-trifluoromethylbenzamide to give the title compound in 94% yield; NMR Spectrum: (DMSOd6) 2.21 (s, 3H), 4.84 (s, 2H), 7.25 (d, 1H), 7.57 (m, 3H), 7.76 (t, 1H), 7.83 (d, 1H), 7.96 (m, 3H), 8.26 (m, 2H), 9.92 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M−H− 445.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[CH3:13][N:14]([CH3:16])[NH2:15]>C(O)C>[CH3:13][N:14]([CH3:16])[NH:15][C:2](=[O:3])[C:1]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:6]
Reactant: CN(C)N
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Product: CN(C)NC(=O)c1ccccc1N
Yield: 29.2 %

Procedure:
Isatoic anhydride (5.0 g, 30.6 mmol), 35 mL of absolute ethanol and anhydrous 1,1-dimethylhydrazine (2.56 mL, 33.6 mmol) were refluxed for 2 hours. The volatiles were removed in vacuo. The residue was purified by silica gel flash chromatography using 5-10% methanol in dichloromethane. Concentration in vacuo produced 1.60 g of 2-aminobenzoic acid N′,N′-dimethylhydrazide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:16](=O)[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13](=[O:15])[CH:14]=[CH:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: O=Cc1ccncc1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(=O)C=Cc2ccncc2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
44 G. of 3',4',5'-trimethoxyacetophenone and 440 ml. of water are heated at 70° C. with stirring and treated with 20.2 ml. of isonicotinaldehyde. Then, there are added, three times at intervals of 30 minutes, 4 ml. each time of a 6% sodium hydroxide solution in water/methaol (2:1). The resulting reaction mixture is kept overnight at 70° C., cooled in an ice-bath and the resulting crystals are filtered off then washed with ethanol and ether to result in a product with a melting point at 124°-127° C. After recrystallization from methanol/ether there are obtained crystals of melting ppont 128°-130° C. The mother liquors are evaporated under reduced pressure, taken up in ethyl acetic and the organic phase is washed twice with water. The washings are extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate and evaporated under reduced pressure. The residue is chromatographed on a 30-fold amount of silica gel (ether/diethylamine 95:5) and after recrystallization from ethanol/ether, there are obtained 3',4',5'-trimethoxy-3-(4-pyridyl)-acrylophenone of melting point 127°-129° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:12])[C:4](=[CH2:13])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:12][C:8]1[CH2:7][CH2:6][CH:5]2[C:9]=1[CH2:10][CH2:11][C:2](=[O:1])[CH2:3][C:4]2=[CH2:13]
Reactant: C=C1CC(O)CCC2=C(C)CCC12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C=C1CC(=O)CCC2=C(C)CCC12
Temperature: 0 °C
Yield: 77.7 %

Procedure:
A solution, cooled to -10°, of 26.7 g of 6-hydroxy-1-methyl-4-methylen-2,3,3a, 4,5,6,7,8-octahydroazulene in 1500 ml of acetone was treated dropwise within 30 minutes with 65 ml of Jones reagent (172 mM CrO3). The mixture was poured on the excess ice-cold bicarbonate solution and exhaustively extracted with ether. The organic phase was washed with bicarbonate solution and water, dried with anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product which was obtained in the form of a yellow oil, was fractionated under reduced presdure and yielded 20.5 g (yield 77%) of pure 1-methyl-4-methylen-6-oxo-2,3,3a, 4,5,6,7,8-octahydroazulene; b.p.0.005 62°-65°; IR(film)νmax = 3090, 1708, 1640, 1450/38, 1345, 1322, 1305, 1262, 1240, 1195, 1140, 1108, 950, 900, 800 cm-1. The compound has a herb-like, camphorous, terpin oil-like odour.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([O:14]CC3C=CC=CC=3)=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]([CH:22]([OH:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCCCC(O)C(C(=O)OCc1ccccc1)c1ccc2c(c1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCC(O)C(C(=O)O)c1ccc2c(c1)OCCO2
Yield: 95.6 %

Procedure:
To a solution of benzyl (2RS,3RS)-2-(1,4-benzodioxan-6-yl)-3-hydroxyheptanoate (720 mg) in methanol (10 ml) was catalytically reduced with 10% palladium on carbon (100 mg) under 3 atmospheric pressure of hydrogen for 1 hour. The catalyst was removed by filtration and the filtrate was evaporated to afford (2RS,3RS)-2-(1,4-benzodioxan-6-yl)-3-hydroxyheptanoic acid (521 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]([O:25]CC)=[O:24])=[N:21][CH:22]=4)[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:28].O[Li].O>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([C:23]([OH:25])=[O:24])=[N:21][CH:22]=4)[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:28]
Reactant: CCOC(=O)c1ncc2ccc(-c3cccnc3-c3ccc(F)c(C)c3)cn12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2ncccc2-c2ccc3cnc(C(=O)O)n3c2)ccc1F
Yield: 77.2 %

Procedure:
Ethyl 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylate (2.1 g) and LiOH.H2O (400 mg) were stirred in THF/H2O (1:1, 60 mL) at 70° C. for 2 h. The reaction mixture was concentrated to dryness and diluted the pale yellow solid with water. The resulting semi-heterogeneous suspension was cooled in ice-bath, stirred and neutralized with aq. 3N HCl to pH 6. The solid aggregate was collected by filtration on Buchner funnel, washed with water and suction dried. Further processing the sample by drying over P2O5 in a vacuum desiccator provided the desired 6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine-3-carboxylic acid (1.5 g, purity: 97%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(O[C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32]C)[CH2:28][CH2:27]1)=O)(C)(C)C>>[CH3:24][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:28][CH2:27]1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Product: CN1CCC(Nc2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 18 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with 4-methylamino-piperidine-1-carboxylic acid tert-butyl ester as described in Example 2 to give the title compound (18% yield). LC-RT 2.20 min.; MS 334 (M+H).
Reaction SMILES: [CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:25][CH:26]1[CH:33]2[CH2:34][C:29]3([CH2:36][OH:37])[CH2:30][CH:31]([CH2:35][CH:27]1[CH2:28]3)[CH2:32]2>>[CH:1]1([S:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:25][CH:26]3[CH:27]4[CH2:35][CH:31]5[CH2:30][C:29]([CH2:36][OH:37])([CH2:34][CH:33]3[CH2:32]5)[CH2:28]4)=[O:21])[CH2:9][CH2:8]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Reactant: O=C(O)c1cccc(OCCC2CCN(S(=O)(=O)C3CC3)CC2)c1
Product: O=C(NC1C2CC3CC1CC(CO)(C3)C2)c1cccc(OCCC2CCN(S(=O)(=O)C3CC3)CC2)c1

Procedure:
Prepared from 3-[2-(1-cyclopropanesulfonyl-piperidin-4-yl)-ethoxy]-benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:24]=3)=[CH:15][CH:14]=2)[CH2:11][C:10]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[N:9]1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=3)=[CH:17][CH:18]=2)[CH2:11][C:10]([C:32]([F:38])([F:37])[C:33]([F:34])([F:35])[F:36])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of 1-(2-chloro-phenyl)-5-[4-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (630 mg, 1.13 mmol) prepared in Example 9 in dichloromethane (6 mL), was slowly added trifluoroacetic acid (867.0 uL, 11.33 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give 680.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[N-:25]=[N+:26]=[N-:27].[Na+].CN(C)C=O>O>[N:25]([C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])=[N+:26]=[N-:27]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N=[N+]=[N-])C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-epoxy-5α-pregnane-11,20-dione (1 g) was added to a mixture of sodium azide (1g), boric acid (1g) and dimethylformamide (20 ml) and the mixture refluxed for 5 hours. The mixture was cooled, poured into water and the resulting emulsion extracted into methylene chloride (2 × 150 ml.). The organic extracts were washed with water (2 × 300 ml.) dried over anhydrous sodium sulphate and evaporated to a red oil which was purified by preparative T.L.C. using ethyl acetate/petrol (1/1), the main band giving 2β-azido-3α-hydroxy-5α-pregnane-11,20-dione (580 mg) as a foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[CH:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[CH:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cc(COC3CCCCO3)cn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cc(COC4CCCCO4)cn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (429 mg, 1.5 mmol) and (RS)-3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K17) (601 mg, 1.5 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (710 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH:32]([F:34])[F:33])=[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]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:9]=2)[CH:7]=1.[C:35]([O:39][C:40](=[O:46])[NH:41][CH2:42][CH2:43][CH2:44]Br)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:35]([O:39][C:40](=[O:46])[NH:41][CH2:42][CH2:43][CH2:44][N:28]1[CH2:27][CH2:26][CH:25]([N:10]2[CH:11]=[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])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:31][CH:32]([F:33])[F:34])=[N:9]2)[CH2:30][CH2:29]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: O=C(Nc1cn(C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 60 °C
Yield: 101.5 %

Procedure:
A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(5-chloro-2-difluoromethoxyphenyl)-1-piperidin-4-yl-1H-pyrazol-4-yl]amide (100 mg, 0.20 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (71 mg, 0.3 mmol) and potassium carbonate (45 mg, 0.32 mmol) in DMF (2 mL) was heated at 60° C. for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with water and extracted with dichloromethane. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated. The resultant residue was chromatographed on silica eluting with dichloromethane on a gradient of 2M ammonia in methanol (0-6%) to give [3-(4-{3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidin-1-yl)propyl]carbamic acid tert-butyl ester as a yellow oil (131 mg, 100%). LCMS (Method 4) [M+H]+=675.0, RT=2.86 min.
Reaction SMILES: [C:1]([C:8]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:9]=1[C:10](N(C)OC)=[O:11])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:22]([Mg]Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:1]([C:8]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:9]=1[C:10](=[O:11])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCCC#Cc1cc(OC)ccc1C(=O)Cc1ccccc1
Yield: 89 %

Procedure:
2-(1-Heptyn-1-yl)-N-methyl-N,4-bis(methyloxy)benzamide (111) (0.58 g, 2.00 mmol) was treated with benzylmagnesium chloride in THF to give 0.57 g (89%) of the title compound (112) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.89 (t, J=7.2 Hz, 3H), 1.30-1.50 (m, 4H), 1.60-1.70 (m, 2H), 2.45 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 4.44 (s, 2H), 6.82 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 6.97 (d, J=2.7 Hz, 1H), 7.19-7.26 (m, 3H), 7.27-7.32 (m, 2H), 7.65 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 321 (M+H)+, m/z 319 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-:12].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCN(C(C)C)C(C)C>C(O)CCC>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[N+:3]([O-:12])=[CH:4][C:5]([CH3:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2cc([N+](=O)[O-])c(C)c[n+]2[O-])c(OC)c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-chloro-5-methyl-4-nitropyridine 1-oxide (1.1 g, 5.8 mmol), 1-(2,4-dimethoxyphenyl)methanamine (1.1 mL, 7.0 mmol), DIEA (2.0 mL, 11.6 mmol), and 1-butanol (9 mL) was subjected to microwave irradiation at 120° C. for 8 h. The reaction mixture was allowed to cool to rt and was filtered. The resulting solid was washed with water (20 mL) and dried to give N-(2,4-dimethoxybenzyl)-5-methyl-4-nitropyridin-2-amine 1-oxide (1.2 g, 67%), which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([O-:17])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[O:9]1[C:8]2[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH2:2][O:24][C:21]3[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[CH:6][C:7]=2[O:12][CH2:11][CH2:10]1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A mixture of 2-bromo-1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)ethanone (1.03 g, 4.00 mmol), 4-nitrophenol (0.57 g, 4.00 mmol), and cesium carbonate (1.63 g, 5.00 mmol) in dry N,N-dimethylformamide (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was diluted with cold water. The resultant solid was collected by filtration gave the title compound (1.19 g, 94%). The product was used in the next step without purification.
Reaction SMILES: [BrH:1].C(O)(=O)C.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[F:6])[N:18]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc(F)cc1F
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-c2csc(Br)n2)c(F)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (25 ml) solution was added to a solution of 2-(2,4-difluorophenyl)-2-oxoethyl thiocyanate (3.39 g, 15.9 mmol) in acetic acid (25 ml), and the mixture was stirred at 130° C. for 2 hours and stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 3.23 g (73.6%) of the desired product as a solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]5[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][N:35]=5)=[O:33])=[CH:27][C:26]=4[N+:41]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>[Fe].C(O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:44])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]5[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][N:35]=5)=[O:33])=[CH:27][C:26]=4[NH2:41])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(NC(=O)c3ccc(Br)cn3)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1cc(NC(=O)c2ccc(Br)cn2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 100 °C

Procedure:
The product from Example 384C (0.20 gm, 0.30 mmol) was suspended in a 4/1 v-v mixture of glacial acetic acid and ethanol (8 ml). To this vigorously stirred suspension was added, in one portion, iron powder (0.215 gm, 3.85 mmol) and the resulting mixture heated under nitrogen in an oil bath at 100° C. After 19.5 hours the reaction mixture was cooled then concentrated under vacuum to a paste which was suspended in water and the solid product collected by vacuum filtration. The cake was washed with water then dried in vacuo at room temperature (0.204 gm, quant.).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[NH2:20][C:21]1[C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[C:24]([C:31]2[O:35][C:34](=[O:36])[N:33]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)[N:32]=2)=[CH:23][C:22]=1[Cl:43]>C(#N)C>[NH2:20][C:21]1[C:26]2[O:27][CH2:28][CH2:29][O:30][C:25]=2[C:24]([C:31]2[O:35][C:34](=[O:36])[N:33]([CH:37]3[CH2:38][CH2:39][N:40]([CH2:14][C:13]4[CH:16]=[CH:17][C:10]([C:9]([F:19])([F:18])[F:8])=[CH:11][CH:12]=4)[CH2:41][CH2:42]3)[N:32]=2)=[CH:23][C:22]=1[Cl:43]
Reactant: Nc1c(Cl)cc(-c2nn(C3CCNCC3)c(=O)o2)c2c1OCCO2
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(-c2nn(C3CCN(Cc4ccc(C(F)(F)F)cc4)CC3)c(=O)o2)c2c1OCCO2
Reaction time: 2 h

Procedure:
1.58 ml (11.38 mmol) of triethylamine and 0.88 g (5.68 mmol) of 4-(trifluoromethyl)benzyl bromide, in solution in 5 ml of acetonitrile, are successively added at room temperature, with magnetic stirring and under an argon atmosphere, to a solution of 1 g (2.84 mmol) of 5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-(piperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one in 60 ml of acetonitrile and the mixture is stirred for 2 h. The solvent is evaporated under reduced pressure, the residue is taken up in chloroform, the solution is washed a number of times with water and dried and the solvent is evaporated under reduced pressure. The residue is crystallized from acetone and 1.14 g of white solid are obtained. Melting point: 198° C.