Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[S:12]([C:37]1[CH:60]=[CH:59][C:40]2=[N:41][N:42]([C:44]3[CH:49]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:47]=[C:46]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:45]=3[OH:58])[N:43]=[C:39]2[CH:38]=1)[C:13]1[CH:36]=[CH:35][C:16]2=[N:17][N:18]([C:20]3[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=3[OH:34])[N:19]=[C:15]2[CH:14]=1.[OH-:61].[Na+].ClC1C=C(C=CC=1)C(O)=O>C(Cl)Cl>[S:12]([C:37]1[CH:60]=[CH:59][C:40]2=[N:41][N:42]([C:44]3[CH:49]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:47]=[C:46]([C:54]([CH3:57])([CH3:56])[CH3:55])[C:45]=3[OH:58])[N:43]=[C:39]2[CH:38]=1)([C:13]1[CH:36]=[CH:35][C:16]2=[N:17][N:18]([C:20]3[CH:25]=[C:24]([C:26]([CH3:27])([CH3:28])[CH3:29])[CH:23]=[C:22]([C:30]([CH3:31])([CH3:32])[CH3:33])[C:21]=3[OH:34])[N:19]=[C:15]2[CH:14]=1)(=[O:6])=[O:61]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Sc4ccc5nn(-c6cc(C(C)(C)C)cc(C(C)(C)C)c6O)nc5c4)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: [OH-]
Agent: O=C(O)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1cc(-n2nc3ccc(S(=O)(=O)c4ccc5nn(-c6cc(C(C)(C)C)cc(C(C)(C)C)c6O)nc5c4)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
A solution of 6.9 g (0.022 mole) of m-chloroperoxybenzoic acid 55% in 50 mL of methylene chloride is added at 25°-27° C. to a solution of 6.8g (0.01 mole) 5,5'-thio-bis-[2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole], prepared in Example 17, in 150 mL of methylene chloride over a period of 15 minutes. The resulting exotherm is controlled with ice cooling. In short order precipitation of product and m-chlorobenzoic acid takes place. After stirring the reaction for 3 hours, there is added 1.2 g (0.03 mole) of sodium hydroxide as a 4% aqueous solution to dissolve the m-chlorobenzoic acid. Methylene chloride is removed from the reaction mixture under partial vacuum and diluted with 75 mL of methanol. The product is filtered and the filter cake thoroughly washed with water and methanol to give 6.5 g. of the title compound, mp.>300° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(#N)C>[N:1]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCOC(=O)CBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccccc21
Reaction time: 0.5 h

Procedure:
Under an atmosphere of nitrogen, a solution of indole (15.0 g, 128 mmol) in dry acetonitrile (300 mL, 0.4 M) was treated with sodium hydride (95%, 3.69 g, 153 mmol) and stirred for 30 min. Ethyl bromoacetate (17.0 mL, 153 mmol) was added in a dropwise manner over 10 min and the solution was stirred at room temperature for 16 h. After concentrating under reduced pressure, the resulting residue was dissolved in ethyl acetate and washed with sat'd. aq. NaCl. The organic extracts were dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography (50% ethyl acetate in heptane): Rf 0.25 (40% ethyl acetate in heptane) 1H NMR (DMSO-d6, 300 MHz) δ 7.53 (d, J=6.3 Hz, 1H), 7.38-7.31 (m, 2H), 7.11 (br t, J=7.2 Hz, 1H), 7.02 (br t, J=7.2 Hz, 1H), 6.45-6.43 (m, 1H), 5.10 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[CH2:9][N:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=[CH2:21])[C:11](=[O:13])[CH3:12].C(N1C2C=CC=CC=2C=CC2N=C(Cl)C(F)=CC=2C1)(=O)C>>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[CH2:9][N:10]([C:11](=[O:13])[CH3:12])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH:20]=[CH:21][C:2]=2[CH:7]=1
Reactant: C=Cc1ccccc1N(Cc1cnc(Cl)cc1Cl)C(C)=O
Agent: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Product: CC(=O)N1Cc2cnc(Cl)cc2C=Cc2ccccc21
Yield: 63.2 %

Procedure:
Compound 41D (117 mg, 63%) was prepared from 41C (210 mg, 0.65 mmol) using a procedure similar to the synthesis of 1D. HPLC Rt=2.519 min; LCMS Found: (M+H)+=285.
Reaction SMILES: Cl.Cl.CN1CCNCC1.CN1CCNCC1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26](O)=[O:27])=[CH:23][C:22]=2[CH:29]=1.O>C1COCC1.CCOCC>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH:26]=[O:27])=[CH:23][C:22]=2[CH:29]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Agent: CN1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=Cc1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
LiA1H4 (3.04 g, 80 mmol) was suspended under stirring at 0° under Ar in anhydrous THF (150 ml), then N-methylpiperazine dihydrochloride (6.92 g, 40 mmol) was added portionwise in 10 minutes. N-methylpiperazine (12 g, 120 mmol) was then added dropwise, the mixture was warmed to RT and stirring continued for 2 hours. The surnatant of this suspension was then added by syringe to a stirred solution at 0° under Ar of 5-chlorobenzofuran-2-carboxylic acid (2.95 g, 15.0 mmol) in anhydrous THF (50 ml). The mixture was refluxed for 4 hours and after cooling to RT the suspension was diluted with Et2O (400 ml). The resulting mixture was poured into water (500 ml) and the organic phase was decanted. The aqueous phase was extracted with Et2O (2×300 ml) and the pooled organic extracts were washed with 2N NaOH (200 ml), 1N HCl (200 ml) and brine (200 ml). After drying (MgSO4) and concentration a brown oily residue was obtained. This was chromatographed on silicagel (n-heptane/EtOAc 3/1). The pooled fractions produced after evaporation pure title compound (850 mg, 4.71 mmol, yield 31.4%) as brown needles.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc(-c2ccccn2)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(-c2ccccn2)nc1CBr
Temperature: 90 °C
Yield: 100.5 %

Procedure:
A mixture of the compound prepared in Example 151 (3.50 g) and N-bromosuccinimide (2.66 g) and benzoyl peroxide (0.362 g) in carbon tetrachloride (80 mL) was heated at 90° C. for 18 hours. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (4.70 g) having the following physical data.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[C:6]([O:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)[C:7]=1[C:8]#[N:9].[C:17]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:22][CH2:21]1)(=O)[CH3:18].ClCCl.N>CO>[CH:11]1([O:10][C:6]2[CH:5]=[C:4]([O:15][CH3:16])[CH:3]=[C:2]([N:1]=[C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:28])[CH2:22][CH2:21]3)[CH3:18])[C:7]=2[C:8]#[N:9])[CH2:14][CH2:13][CH2:12]1
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Reactant: COc1cc(N)c(C#N)c(OC2CCC2)c1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OC2CCC2)c1

Procedure:
The subtitle compound was prepared from 3-amino-4-cyano-5-cyclobutyloxyanisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 14(d) (93%). Rf 0.52 (dichloromethane:methanol:0.880 aqueous ammonia, 92:7:1, v/v). MS m/z 456 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3cnn(C)c3)ccc21
Product: CC1c2ccc(-c3cnn(C)c3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl-].[CH2:2]([NH+:9]1[CH2:13][CH:12](S(C2C=CC=CC=2)=O)[C:11]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)([C:22]([F:25])([F:24])[F:23])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH2:2]([N:9]1[CH:13]=[CH:12][C:11]([C:26]2[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=2)([C:22]([F:25])([F:24])[F:23])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(c1ccccc1)C1C[NH+](Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)C=CN(Cc2ccccc2)C1
Yield: 34.8 %

Procedure:
1-Benzyl-3-(3,5-dichlorophenyl)-4-(phenylsulfinyl)-3-(trifluoromethyl)pyrrolidinium chloride (1.00 g, 82% purity, 1.53 mmol) is suspended in toluene (3 mL) under a nitrogen atmosphere. Sodium carbonate (810 mg, 7.65 mmol) was added and the mixture was heated to reflux for 2.5 hours. After cooling water was added, the phases were separated and the aqueous phase was extracted twice with toluene. The combined organic phases were dried over sodium sulphate, filtered and the solvent evaporated. The residue was repeatedly crystallized from n-heptane to yield 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-2,3-dihydro-1H-pyrrole (198 mg, 89% purity, 31% yield).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C(F)=NC(F)=NC=1[F:22].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([F:22])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)F

Procedure:
BOC-Phe (1 mmole) in dry CH2Cl2 under nitrogen is treated with cyanuric fluoride (8 mmol) and pyridine (1 mmole) to form the above-identified product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[NH2:13][C@H:14]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C@H:15]1[CH2:26][C:27]([O:29]CC)=[O:28]>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:13][C@H:14]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C@H:15]1[CH2:26][C:27]([OH:29])=[O:28])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)C[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1N
Solvent: CN(C)C=O
Product: O=C(O)C[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of indole-2-carboxylic acid in DMF is added 1 equivalent of 1,1-carbonyldiimidazole. After stirring for 4 h at room temperature a solution of the aminopyrrolidinone of Example 68 in DMF is added. After stirring for 12 h at room temperature the reaction mixture is evaporated in vacuo to give a residue which is chromatographed on silica gel to give the desired amide. To a solution of the amide in 1:4 EtOH/THF is added a solution of lithium hydroxide (1.4 equiv) in H2O and the resulting solution is stirred for 2 h at room temperature. The reaction mixture is then acidified to pH=2 with 1N HCl. Removal of the solvent gives a residue which is chromatographed on silica gel to give the title carboxylic acid as a single enantiomer.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-[(trans-4-hydroxycyclohexyl)amino]quinazoline-7-carboxylate (3090 mg, 10.3 mmol) in THF (100 mL) was added MeOH (20 mL) followed by 2 M NaOH (20 mL, 40 mmol) and the mix stirred at R.T. for 3 hours. The solvents were stripped and the mix acidified with a stoichiometric amount of 1 M HCl giving a yellow precipitate that was filtered off and washed with water and air dried to yield the title compound as a bright yellow solid, 2.7 g, 92%. 1H NMR (400 MHz, DMSO-D6) δ ppm 13.30 (1H, s) 9.17 (1H, s) 7.96 (1H, s) 7.85 (1H, d, J=8.34 Hz) 7.64 (1H, d, J=8.34 Hz) 7.48 (1H, s) 4.57 (1H, s) 3.79 (1H, s) 1.79-2.04 (4H, m) 1.17-1.43 (4H, m); MS (API−) for C15H17N3O3 m/z 286.1 (M−H)+.
Reaction SMILES: [C:1](=[O:7])([O-:6])[O:2][CH2:3][CH:4]=[CH2:5].CO.[Br:10]Br.[OH-].[Na+]>O>[C:1](=[O:2])([O-:7])[O-:6].[CH2:5]([CH:4]1[O:2][CH2:3]1)[Br:10]
Reactant: BrBr
Reactant: C=CCOC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: BrCC1CO1
Product: O=C([O-])[O-]
Temperature: 60 °C
Yield: 54 %

Procedure:
Into a 500-ml flask are placed 36 g of bis(allyl carbonate (0.25 mole) and 100 ml of methanol. This mixture is stirred and cooled in an ice water bath while 80 g of bromine (0.5 mole) is added dropwise. When this reaction is complete, 11 ml of water is added and the mixture stirred while 44 g of a 50 percent aqueous solution of sodium hydroxide (0.55 mole) is added at such a rate so as to maintain reaction temperatures below 55° C. The mixture is then heated to 60° C. for 4 hours and allowed to cool. To this mixture is added 250 ml of water and the resulting water phase is extracted twice with 150-ml portions of methylene chloride. The products are combined and dried over sodium sulfate, filtered and distilled to give a 100 percent conversion of carbonate and 54 percent yield of epibromohydrin. No detectable dibromopropene appeared to be formed.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=1)[C:13]([N:15]([CH2:26][C:27](O)=[O:28])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:56][C:57]([CH3:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:58][NH2:59].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:13](=[O:14])[N:15]([CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:26][C:27](=[O:28])[NH:59][CH2:58][C:57]([CH3:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH3:56])[CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCN(CC(=O)O)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Reactant: CC(C)(CN)c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(CC(=O)NCC(C)(C)c1ccccc1)C(=O)[C@H](Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
The compound from Step 3 (1.3 g, 1.8 mmol) was dissolved in methylene chloride (10 mL). β,β-dimethylphenethylamine hydrochloride (Example 1, Step 6) (0.370 g, 2 mmol) was added followed by diisopropylethylamine (1 mL, 5.7 mmol) and PyBOP (1.04 g, 2 mmol) dissolved in methylene chloride (10 mL). The reaction was stirred overnight at room temperature. The solution was concentrated, the residue taken up in ethyl acetate and washed three times with saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated to give a white solid; 1.09 g (70% yield). MS-APCI: M+1=863.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[CH:5]([C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[O:9][CH2:10][C:11](=[CH2:16])[C:12]([O:14][CH3:15])=[O:13])=O.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>C(O)(C)(C)C.O>[F:21][C:22]([F:32])([F:33])[C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30]([N:3]2[CH2:16][C:11]3([C:12]([O:14][CH3:15])=[O:13])[CH2:10][O:9][C:8]4[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=4[CH:5]3[NH:4]2)=[O:31])=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: NN
Reactant: C=C(COc1ccccc1C=O)C(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)C12COc3ccccc3C1NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
A solution of 7.15 g (0.0681 mol) of hydrazine dihydrochloride in 95 mL of tert-butanol and 5 mL of water was heated at reflux for 1/2 hour at which time 1.50 g (0.0068 mol) of the product from Step A was added all at once. The reaction mixture was refluxed for 20 hours and the solvent was removed by evaporation under reduced pressure. 200 mL of 1N sodium hydroxide was added and the crude product was extracted with ethyl acetate (3×75 mL). The ethyl acetate was washed with water (100 mL), dried over anhydrous magnesium sulfate, filtered into a flask containing 1.27 g (0.0068 mol) of α,α,α-trifluoro-p-tolylisocyanate. The reaction mixture was stirred at room temperature for 1/2 hour, the solvent was removed under reduced pressure and the crude product was chromatographed using ether/hexanes (35%:65%) as eluent to afford 0.219 g of a white solid; mp 211°-212° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4].[F:9][C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=1[C:18](=[CH2:22])[C:19](=[O:21])[CH3:20].[C:23](O[Li])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]1([C:26](=[N:1][CH:2]([CH2:22][CH:18]([C:11]2[C:12]([F:17])=[CH:13][CH:14]=[C:15]([F:16])[C:10]=2[F:9])[C:19](=[O:21])[CH3:20])[C:3]([O:5][CH:6]([CH3:8])[CH3:7])=[O:4])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:25]=[CH:22][CH:18]=[CH:19][CH:24]=1
Reactant: CC(C)OC(=O)CN
Reactant: [Li]OC(C)(C)C
Reactant: C=C(C(C)=O)c1c(F)ccc(F)c1F
Solvent: C1CCOC1
Product: CC(=O)C(CC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)C)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diphenylidene isopropyl glycinate (2.0 g, 7.0 mmol) and 31 (1.4 g, 7.0 mmole) were dissolved in THF (10 ml). The solution was cooled to −10° C. tert-BuOLi (0.56 g, 7.0 mmole) was charged into the solution in several portions. The reaction was warmed up to room temperature slowly and stirred overnight. After quenched by addition of aqueous NH4Cl, the solvents were removed by distillation under vacuum. The residue was subjected to silica chromatography column eluted by hexane and EtOAc yielding 32 (3.0 g, 89%) as an oil, which was directly used in the next step.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:35][C:36]1[CH:46]=[CH:45][C:39]([CH2:40][NH:41][CH:42]2[CH2:44][CH2:43]2)=[C:38]([O:47][C@H:48]([CH2:50][CH:51]=[CH2:52])[CH3:49])[CH:37]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:41]([CH:42]4[CH2:44][CH2:43]4)[CH2:40][C:39]4[CH:45]=[CH:46][C:36]([CH3:35])=[CH:37][C:38]=4[O:47][C@H:48]([CH2:50][CH:51]=[CH2:52])[CH3:49])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1CNC1CC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN(Cc4ccc(C)cc4O[C@@H](C)CC=C)C4CC4)nn23)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (95 mg, 0.163 mmol) in acetonitrile (3 mL) at 0° C. was added (S)—N-(4-Methyl-2-(pent-4-en-2-yloxy)benzyl)cyclopropanamine (40 mg, 0.163 mmol) and Hunig's Base (0.028 mL, 0.163 mmol). It was stirred at 0° C. for 2 h and then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was then purify by 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((cyclopropyl(4-methyl-2-((S)-pent-4-en-2-yloxy)benzyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.128 mmol, 79% yield) as an oil. LCMS (M+1)=702.5.
Reaction SMILES: [CH3:1][C:2]([NH2:11])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)[CH3:3].C=O.[C:14](=O)([O-])O.[Na+]>>[CH2:14]=[N:11][C:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[CH:5]=1)[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(N)c1cccc(Cl)c1
Agent: C=O
Agent: [Na+]
Product: C=NC(C)(C)c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
1-Methyl-1-(3-chlorophenyl)ethylamine (5.0 g) was added slowly to formalin (aqueous 37% HCHO solution) (3.5 g) at room temperature. This was allowed to react as it was for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, which was then extracted with ether. After it was washed with saturated saline, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the captioned compound (5.6 g) as syrup.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[O:23][C:24]([CH3:27])=[CH:25][CH:26]=1)#[CH:21].C(N(CC)CC)C.O>O1CCOCC1>[C:1]1([S:7]([N:10]2[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:21]=[C:20]2[C:22]2[O:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccc(C)o1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1cnc2c(c1)cc(-c1ccc(C)o1)n2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 2-benzenesulfonylamino-5-methylthio-3-iodopyridine (203 mg) in 1,4-dioxane (5 ml), 2-ethynyl-5-methylfuran (160 mg), bistriphenylphosphine palladium dichloride (18 mg), cuprous iodide (10 mg) and triethylamine (75 mg) were added successively and the mixture was stirred in a sealed tube at 60° C. for 1 hour. After cooling, the reaction solution was poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=5:1) to obtain 169 mg of the desired products as a brown oil.