Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.CC#N>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:21])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc3[nH]ccc3n12
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1nnc2ccc3c(ccn3C(C)c3ccccc3)n12
Temperature: 45 °C

Procedure:
To a mixture of 1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10 mg, 0.058 mmol, isolated from Example 2, Step 5 during a preparation wherein the methylation of Step 2 of that Example was incomplete) and K2CO3 (0.024 g, 0.17 mmol) in DMF (0.22 mL) was added 1-(bromoethyl)benzene (12 μL, 0.087 mmol, Acros). The mixture was heated to 45° C. for 3 hours. The mixture was diluted with MeCN and filtered, then the product was isolated by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (3.3 mg, 20%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[CH:15][S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].CC(O)=O.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([CH2:17][OH:18])=[C:15]([Br:30])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CC2Cc3c(CO)csc3C2C1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC2Cc3c(sc(Br)c3CO)C2C1
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of the product from Example 17, step c) (199 mg, 0.79 mmol) in CHCl3 (3 ml) and AcOH (3 ml) was added NBS (156 mg, 0.88 mmol). The reaction mixture was stirred for 30 minutes, quenched with saturated NaHCO3 (10 ml), and extracted with EtOAc (20 ml). The EtOAc layer was dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product that was purified by silica-gel preparative TLC (hexanes:EtOAc-3:1) providing the subtitle compound (99.6 mg, 36%). 1H NMR (300 MHz, CDCl3, ppm) 1.22 (t, J=7 Hz, 3H); 2.42 (br s, 1H); 2.63-2.78 (m, 1H); 2.95-3.18 (m, 2H); 3.30-3.48 (br m, 1H); 3.50-3.72 (br m, 2H); 3.75-3.88 (br m, 2H); 4.08 (q, J=7 Hz, 2H); 4.52 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]([C:16]2[N:20]=[C:19](C(Cl)(Cl)Cl)[O:18][N:17]=2)[N:10]=1.Cl.[CH:32]1([CH2:35][O:36][CH2:37][CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1>CN(C=O)C>[CH:32]1([CH2:35][O:36][CH2:37][CH:38]2[CH2:43][CH2:42][N:41]([C:19]3[O:18][N:17]=[C:16]([C:11]4[N:10]=[C:9]([N:8]([CH3:7])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:14]=[C:13]([NH2:15])[N:12]=4)[N:20]=3)[CH2:40][CH2:39]2)[CH2:33][CH2:34]1
Reactant: C1CC(COCC2CC2)CCN1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(N3CCC(COCC4CC4)CC3)n2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
Potassium carbonate (0.107 g, 0.776 mmol) and 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.150 g, 0.388 mmol) were added to a solution of 4-[(cyclopropylmethoxy)methyl]piperidine hydrochloride salt (Intermediate 198, 0.160 g, 0.776 mmol) in DMF (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 h and then evaporated under vacuum to remove the DMF. The crude residue was dissolved in EtOAc (5 mL) and washed with water (3×3 mL). The aqueous washes were combined, re-extracted with EtOAc (2×3 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to provide a crude brown residue which was purified by preparative HPLC, Method B, to afford the title compound as an off-white solid (28 mg, 16%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])=[O:15])[N:10]([CH2:23][CH:24]([CH3:26])[CH3:25])[N:9]=[CH:8]2.N[C:33]1C(=O)NC=CC=1.C(N(C(C)C)C(C)C)C.C(O)C(N)(CO)CO>ClCCl>[F:1][C:2]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:16][C:17]1[C:18](=[O:22])[NH:19][CH:20]=[CH:33][CH:21]=1)=[O:15])[N:10]([CH2:23][CH:24]([CH3:25])[CH3:26])[N:9]=[CH:8]2
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Reactant: Nc1ccc[nH]c1=O
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)Nc3ccc[nH]c3=O)cc21
Reaction time: 48 h
Yield: 32.3 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylate (Example 16; 100 mg, 0.226 mmol) in dichloromethane (1.1 mL) was added 3-aminopyridin-2(1H)-one (26.1 mg, 0.237 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.039 mL, 0.226 mmol). After 48 h, the reaction was treated with tris-amine resin (silica supported amine 3, 100 mg, loading=1.76 mmol/g). After 45 minutes, the reaction was filtered though a silica gel plug, washing well with ethyl acetate. The filtrate was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The organics were dried with sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with a gradient of 50% to 100% ethyl acetate/hexanes to yield 5-(2,4-difluorophenoxy)-1-isobutyl-N-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indazole-6-carboxamide (32 mg, 32%). Mass spec: 439 (M+1). 1H NMR (CDCl3) δ 10.8 (s, 1H), 8.68 (dd, 1H), 8.42 (s, 1H), 7.89 (s, 1H), 7.28-6.88 (m, 6H), 6.36 (dd, 1H), 4.25 (d, 2H), 2.38 (m, 1H), 0.95 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][CH2:16][N:17]([CH3:19])[CH3:18])=[C:10]([Cl:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:27]>ClCCl>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:27])[CH:15]=[CH:16][N:17]([CH3:18])[CH3:19])=[C:10]([Cl:20])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN(C)CC#Cc1ccc(NC(=O)OC(C)(C)C)cc1Cl
Solvent: ClCCl
Product: CN(C)C=CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice cold solution of [3-chloro-4-(3-dimethylamino-prop-1-ynyl)-phenyl]-carbamic acid tert-butyl ester (4.0 g) in dichloromethane (30 ml) is added in small portions 3-chloroperoxybenzoic acid (2.34 g). After the reaction is stirred at 0° C. for 20 minutes, the mixture is passed over twenty weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and the N-oxide is eluted using a solution of 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness under reduced pressure. The residue is treated successively three times with small portions of methanol (ca. 50 ml) followed by evaporation to near dryness under reduced pressure, and the volume of the solution is adjusted to 250 mL by addition of methanol. The methanolic solution of the N-oxide is then heated to reflux for approximately 15 hours, then cooled, and the solvent is evaporated to dryness under reduced pressure. The residue is purified by chromatography over silica gel (80% ethyl acetate in hexanes is used as the eluant) to give the desired product as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:1][C:2]1[N:7]=[C:6]2[S:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc2ccsc2nc1N
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1nc2ccsc2nc1NCc1ccccc1
Yield: 61.6 %

Procedure:
Ethyl 3-aminothieno[2,3-b]pyrazine-2-carboxylate (0.450 g, 2.02 mmol) was treated with neat NaH (0.058 g, 2.42 mmol) and benzyl bromide (0.380 g, 2.22 mmol) as described in Example 94A. Purification by column chromatography on silica gel eluting with a solvent gradient from 10:1 to 3:1 hexanes:ethyl acetate gave the title compound (0.39 g, 62%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ1.39 (t, 3H), 4.37 (q, 2H), 5.38 (d, 2H), 7.19-7.42 (m, 5H), 7.88 (br t, 1H), 8.55 (m, 2H). MS (DCI/NH3) m/e 3 14 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][NH:9][C:10]([C@@H:12]2[N:17]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:16][CH2:15][N:14]([C:31]3[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=3)[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH3:42]>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:13][N:14]([C:31]3[S:32][C:33]([C:37](=[O:38])[NH2:42])=[C:34]([CH3:36])[N:35]=3)[CH2:15][CH2:16][N:17]2[S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[O:11])=[CH:40][CH:41]=1)([CH3:2])[CH3:3]
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)sc1C(=O)O
Reactant: N
Solvent: C1CCOC1
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)cc3)C2)sc1C(N)=O
Temperature: 25 °C

Procedure:
To a solution of the compound (30 mg) obtained in Example 6 in tetrahydrofuran (0.3 ml) was added, with stirring at room temperature, N,N′-carbonyldiimidazole (10 mg). After stirring at room temperature for 3 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring at room temperature for 2.5 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring at room temperature for 2.5 hr, 28% aqueous ammonia solution (10 μl) was added. After stirring overnight at room temperature, the reaction mixture was partitioned by adding ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (10% methanol/chloroform) to give the title compound (20 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11](O)[C:10]3[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:20]=1.[Cl-:21].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:21][CH:11]1[C:10]2[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=2[S:8][C:7]2[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[CH2:12]1
Reactant: [Cl-]
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(O)C2
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(Cl)C2
Reaction time: 3 h

Procedure:
15.7 G. of 10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-ol, 250 ml. of benzene and 6 g. of finely powdered calcium chloride are saturated with hydrogen chloride gas at 15° C. within 2.5 hours and then stirred for an additional 3 hours. After the addition of 0.8 g. of active carbon, the precipitate is removed by filtration and washed with benzene. The benzene phase is evaporated under reduced pressure, and there is obtained 10-chloro-10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin having a melting point of 120°-123° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:9]([OH:11])=[O:10].[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2>CN(C)C=O.C(Cl)(Cl)Cl>[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19]([O:10][C:9](=[O:11])[C:8](=[O:7])[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[CH2:18]2
Reactant: O=C(O)C(=O)c1cccs1
Reactant: O[C@H]1CN2CCC1CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
Oxalyl chloride (1.34 ml, 0.0154 mol) was added to a solution of oxothien-2-yl-acetic acid (2 g, 0.0128 mol) and dimethylformamide (one drop) in 30 ml of chloroform (etanol free) at 0° C. The mixture was stirred and allowed to warm at room temperature. After one hour the solvent was evaporated. The residue was dissolved in chloroform and evaporated again. This procedure was repeated two times. The product obtained was disolved in CHCl3 (30 ml) and a solution of 3(R)-quinuclidinol (1.95 g, 0.0154 mol) in CHCl3 (30 ml) was added to this at 0° C. The mixture was stirred and allowed to warm at room temperature. After 1.5 h at r.t., the mixture was washed with 10% aqueous potassium carbonate, then with water, dried over Na2SO4 and evaporated to give 3.14 g (92.6%) of the title compound as a yellow oil. 1H-NMR (CDCl3): δ 1.40-1.50 (m, 1H), 1.50-1.70 (m, 1H), 1.70-1.80 (m, 1H), 1.90-2.0 (m, 1H), 2.15 (m, 1H), 2.70-3.05 (m, 5H), 3.30-3.40 (m, 1H), 5.05 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H), 8.10 (m, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[C:21]([OH:22])=[CH:20][C:10]2[CH2:11][C:12]3([O:19][C:9]=2[CH:8]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:6])([CH3:5])[CH3:4].[CH2:23](Cl)[C:24](=[CH2:26])[CH3:25]>CN(C)C=O>[C:3]([C:7]1[C:21]([O:22][CH2:25][C:24]([CH3:26])=[CH2:23])=[CH:20][C:10]2[CH2:11][C:12]3([O:19][C:9]=2[CH:8]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1cc2c(cc1O)CC1(CCCCCC1)O2
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2

Procedure:
0.13 g of oily sodium hydride and 0.74 g of 6-t-butyl-5-hydroxy-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane synthesized in Example 7 were treated with 0.32 ml of methallyl chloride in dimethylformamide in the same manner as in Example 8-1) to give 0.89 g of 6-t-butyl-5-(2-methyl-2-propenyloxy)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a colorless oil (quantitative).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:18]Br>C(O)(=O)C.O>[Br:18][C:9]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:8]=1[NH2:10]
Reactant: Cc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccccc1-n1nc(C(C)(C)C)c(Br)c1N
Reaction time: 0.08 h
Yield: 73.3 %

Procedure:
To a solution of 3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (1.00 g, 4.36 mmol) in acetic acid (10 mL) was added bromine (662 mg, 0.21 mL, 4.14 mmol) dropwise. The reaction mixture was stirred for 5 min, and then diluted with water (50 mL), causing a solid to precipitate. The solid was collected by filtration, then dissolved in EtOAc (50 mL). The EtOAc solution was then washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated under reduced pressure to afford the product (935 mg, 70%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 1.32 (s, 9H), 2.04 (s, 3H) 5.02 (s, 2H), 7.20-7.38 (m, 4H). ES-MS m/z 308.6 (MH+); HPLC RT (min) 3.15.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].C1C=CC(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=CC=1>C1COCC1>[F:34][C:33]([F:36])([F:35])[S:30]([O:22][C:19]1[CH2:18][CH2:17][N:16]([C:13](=[O:15])[CH3:14])[CH2:21][CH:20]=1)(=[O:32])=[O:31]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (18.0 mL, 128 mmol) was taken up in 50 mL of THF and chilled to −78° C. Butyllithium, 2.5 M in hexanes (51.0 mL, 128 mmol) was added dropwise. After 10 min, 1-acetylpiperidin-4-one (15.0 g, 106 mmol) was added in 60 mL of THF with rigorous stirring. After 30 min, n-phenyltriflamide (41.8 g, 117 mmol) was added in 120 mL of THF. The reaction mixture was stirred at −78° C. to RT for 16 h. The reaction mixture was quenched by saturated NaHCO3, followed by extraction with EtOAc and 5% citric acid. The organic layer was washed with 1 N NaOH (2×), water (2×), and brine, then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% to 60% EtOAc/hexanes) afforded 1-acetyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([C:9]([NH:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O>CCOCC>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([C:9]2[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[N:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CO)NC(=O)c1ccc(C(C)(C)C)cc1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CC1(C)COC(c2ccc(C(C)(C)C)cc2)=N1
Temperature: 25 °C

Procedure:
All of the 4-tert-butyl-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzamide prepared above (174 mmol) was charged into a 500 mL round bottom flask fitted with a stir bar and septum. Established and maintained nitrogen atmosphere. Added 50 mL (685 mmol) of thionyl chloride dropwise over 20 min. Warmed the flask with a heat gun to dissolve some of the resin and initiate the reaction. The reaction mixture solidified. Warmed the flask with a heat gun to dissolve all the solids. Cooled to room temperature. Poured the reaction solution in a thin stream into 500 mL of stirred Et2O. A white precipitate formed. Collected the precipitate by filtration and washed thoroughly with Et2O. Dissolved the collected solids in 300 mL water and neutralized with 25% NaOH. Extracted the yellow aqueous solution with 2×200 mL Et2O. Washed the yellow extracts with 200 brine, dried over MgSO4, and removed the solvent on rotavap to obtain 28.50 g of the title compound as a waxy white solid. MS (ESI) 232 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:6][CH2:7][CH:8]([CH3:41])[O:9][C:10]1[CH:11]=[C:12]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.C(O)C.[OH-].[Na+]>[C:48]([Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[O:6][CH2:7][CH:8]([CH3:41])[O:9][C:10]1[CH:11]=[C:12]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:38])=[O:39])=[CH:35][CH:36]=2)[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][N:23]=1)=[CH:15]2)([CH3:51])([CH3:49])[CH3:50]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC(C)CO[Si](c4ccccc4)(C(C)(C)C)C(C)(C)C)c3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(CO[Si](c1ccccc1)(C(C)(C)C)C(C)(C)C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Ethyl (2-{7-(2-{[di-tert-butyl(phenyl)silyl]oxy}-1-methylethoxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl)acetate (480 mg) was dissolved in a mixed solvent of tetrahydrofuran (10 mL)-ethanol (10 mL), 1M aqueous sodium hydroxide solution (7 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The precipitated solid was collected by filtration to give the title compound (320 mg, yield 70%) as a yellow solid. MS 743 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[C:29](=[O:30])[N:28]([CH3:31])[C:21]4[N:22]=[C:23](SC)[N:24]=[CH:25][C:20]=4[CH:19]=3)[CH:15]=[CH:14][C:13]=2[F:32])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37][NH2:38].C1COCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[C:29](=[O:30])[N:28]([CH3:31])[C:21]4[N:22]=[C:23]([NH:38][CH3:37])[N:24]=[CH:25][C:20]=4[CH:19]=3)[CH:15]=[CH:14][C:13]=2[F:32])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34]
Reactant: CN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c(=O)n(C)c2n1
Yield: 67 %

Procedure:
Using a procedure analogous to Example A1, 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (55 mg, 0.100 mmol) and 2.00N methylamine in THF (4.00 mL, 8.0 mmol) were combined to provide 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (36 mg, 67% yield). 1H NMR (300 MHz, DMSO-d6): δ 2.90 (s, 3 H), 3.53-3.61 (m, 3 H), 7.26-7.31 (m, 2 H), 7.58-7.59 (m, 2 H), 7.60-7.75 (br. m, 1 H), 7.88 (s, 1 H), 8.10 (s, 1 H), 8.33-8.35 (m, 1 H), 8.64-8.77 (m, 2 H), 9.49 (s, 1H); MS (ESI) m/z: 521.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.CC(C)([O-])C.[K+].[O:16]1[CH2:21][CH2:20][CH2:19][O:18][CH:17]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3Cl)[CH:29]=2)=[N:26][CH:27]=1>CS(C)=O.O>[O:16]1[CH2:21][CH2:20][CH2:19][O:18][CH:17]1[C:22]1[CH:23]=[CH:24][C:25]([C:28]2[S:36][C:35]3[C:30](=[N:31][CH:32]=[CH:33][C:34]=3[O:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=3[F:9])[CH:29]=2)=[N:26][CH:27]=1
Reactant: Nc1ccc(O)c(F)c1
Reactant: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a solution of 4-amino-2-fluorophenol (4) (7.42 g, 58.4 mmol) in DMSO (65 mL) was added potassium tert-butoxide (7.75 g, 69.0 mmol)). After 30 min, intermediate 29 (17.67 g, 53.1 mmol) was added and the reaction mixture was heated at 100° C. for 1.5 h, cooled down to room temperature, poured in water (300 mL) at 40-45° C. and stirred for 30 min. The solid was collected by filtration, washed with water (2×30 mL) and dried for 2 h. This material was triturated with ether (60 mL), to afford intermediate 31 (19.80 g, 88% yield) as a brown solid. MS (m/z): 424.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[N-:9]=[N+:10]=[N-:11].[Na+].O>CS(C)=O>[N:9]([C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8])=[N+:10]=[N-:11]
Reactant: O=Cc1sccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=Nc1ccsc1C=O
Temperature: 65 °C
Yield: 76.1 %

Procedure:
3-Bromothiophene-2-carbaldehyde (1) (2000 mg, 10.47 mmol) was treated with sodium azide (1994 mg, 30.7 mmol) in DMSO (27 ml). The reaction was heated to 65° C. for 48 h in a sealed 40 mL vial. The reaction mixture was then taken up into H2O (35 mL) and extracted with diethyl ether (3×20 mL). The organic product layer was washed with 25 ml of saturated NaCl solution, dried over Na2SO4, and concentrated in vacuo to give 3-azidothiophene-2-carbaldehyde (1.22 g, 76% yield).
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][C:12]#[N:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].B#B>C1COCC1>[CH3:1][CH:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(OCC#N)cc1
Agent: B#B
Solvent: C1CCOC1
Product: CCC(C)Oc1ccc(OCCN)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the above phenoxyacetonitrile (7.21 g, 35.2 mmol) in 60 ml of THF at 8° is added 1M diborane (61.50 g, 61.5 mmol) over 45 min. The reaction is warmed to RT and stirred for 6 hours. The reaction is stirred for 16 hours. The THF-H2O is removed in vacuo and water and ether are added to the white solid, followed by 10% aqueous sodium hydroxide to basify. The product is extracted with ether (3×) and the combined organic phases are washed with water and with brine, dried, filtered and solvent removed to give 2-[4-(1-methylpropoxy)phenoxy]ethylamine.