Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16]([CH2:20][CH2:21][C:22](Cl)=[O:23])([O:18][CH3:19])=[O:17]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:22](=[O:23])[CH2:21][CH2:20][C:16]([O:18][CH3:19])=[O:17])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: COC(=O)CCC(=O)Nc1nc2cccc(-c3ccoc3)n2n1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 3-carbomethoxypropionyl chloride (65 mg, 0.60 mmol; 2.0 eq.) as a white powder (83.5 mg, 88%). HPLC, Rt: 2.40 min. (purity 95.4%). LC/MS, M−(ESI): 313.2.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:8]1[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 59 %

Procedure:
Sodium borohydride (0.2 g) was added portionwise to a solution of 4'-acetyl-2'-(2,4-difluorophenylamino)methanesulfonanilide (1.5 g) in methanol (15 ml) at 5° to 10° C. The mixture was stirred for 10 hours at room temperature, treated with acetic acid, and concentrated. The residue was triturated with water and filtered. The solid (1.6 g) was recrystallized from a mixture of ethanol and ethyl acetate to give colorless needles of 2'-(2,4-difluorophenylamino)-4'-(1-hydroxyethyl)methanesulfonanilide (0.89 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)[S:17][C:10]=12.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[NH:39][C:40](=[O:45])[CH2:41][C:42](O)=[O:43].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:42](=[O:43])[CH2:41][C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[O:45])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Reaction time: 0.08 h
Yield: 50.4 %

Procedure:
To a solution of amine 54 (260 mg, 0.57 mmol, crude) in DMF (6 mL), were added acid 27 (108 mg, 0.52 mmol) and HOBt (77 mg, 0.57 mmol). After stirring for 5 min, EDC (120 mg, 0.63 mmol) was added, and the reaction mixture was stirred at room temperature for additional 4 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Aquasil C-18, gradient, MeOH 60% to MeOH 95% in water) to afford title compound 48 (160 mg, 46% yield) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.87 (bs, 1H), 10.75 (s, 1H), 9.62 (s, 1H), 8.60 (d. 1H), 8.17 (s, 1H), 8.02 (m, 3H), 7.89 (d, 1H), 7.74 (d, 2H), 7.51 (m, 1H), 7.05 (m, 2H), 6.90 (t, 1H), 6.79 (d, 1H), 4.39 (d, 1H), 6.57 (d, 1H), 3.84 (s, 2H), 3.69 (s, 2H), 3.35 (m, 2H), 3.06 (m, 3H), 2.00 (m, 2H), 1.87 (m, 2H). MS (m/z): 610.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(N)cn2)C1
Yield: 37.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with tert-butyl 3-aminopiperidine-1-carboxylate (695 mg, 3.5 mmol) followed by reduction to afford the desired product (337 mg, 35%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[CH:32]=[C:33]([CH:38]2[CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1.O>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH:2]=[O:3])[CH2:40][CH2:39]2)[CH:34]=[C:35]([F:37])[CH:36]=1
Reactant: O=C1CCC(c2cc(F)cc(F)c2)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C[C@H]1CC[C@H](c2cc(F)cc(F)c2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In an argon atmosphere, 263 g of methoxymethyl triphenylphosphonium chloride was suspended in THF (800 mL), and 90 g of potassium-tert-butoxide was added the resultant suspension at an inside temperature of 0° C. or less, followed by stirring at an inside temperature of 0° C. for 20 minutes. Then, a solution of 4-(3,5-difluorophenyl)cyclohexanone (119 g) in THF (300 mL) was added at an inside temperature of 5° C. or less, followed by stirring at an inside temperature of −5 to 8° C. for 30 minutes. After water (10 mL) was added, the solvent was distilled off under reduced pressure, and water (400 mL), methanol (400 mL), hexane (500 mL), and 7.3 g of a 70% aqueous tert-butyl hydroperoxide solution were added to the residue, followed by stirring at room temperature for 1 hour. An organic layer was separated and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with a 50% aqueous methanol solution and water two times in that order, and the solvent was distilled off under reduced pressure. Then, 10% hydrochloric acid (400 mL) and THF (400 mL) were added to the resultant residue, followed by heating under reflux for 1 hour. An organic layer was separated and an aqueous layer was subjected to extraction with ethyl acetate. The ethyl acetate extract was combined with the organic layer and washed with saturated brine two times. The solvent was distilled off under reduced pressure, and methanol (300 mL) and a 10% aqueous sodium hydroxide solution (20 mL) were added to the resultant residue, followed by stirring at 5° C. to −15° C. for 1 hour. The mixture was neutralized with 10% hydrochloric acid, and then water (300 mL), THF (200 mL), and ethyl acetate (400 mL) were added to the mixture. An organic layer was washed with saturated brine two times and then dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to yield 112 g of trans-4-(3,5-difluorophenyl)cyclohexane carbaldehyde as a light yellow oil.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:9]([CH3:18])=[C:10]([CH:14]=[C:15]([F:17])[CH:16]=1)[C:11]([OH:13])=[O:12].IC>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[C:9]([CH3:18])=[C:10]([CH:14]=[C:15]([F:17])[CH:16]=1)[C:11]([O:13][CH3:1])=[O:12]
Reactant: Cc1c(Br)cc(F)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(F)cc(Br)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
K2CO3 (1.2 eq.) was added to a solution of (E3) in DMF (0.26 M) and the resulting suspension was stirred at RT for 30 min. Then, iodomethane (1.2 eq.) was added and the reaction mixture was stirred at RT overnight. The solution was diluted in EtOAc and the organic phase was washed with brine and dried (Na2SO4). Solvent was removed in vacuo giving a residue that was purified by flash chromatography column on silica (EtOAc/Petroleum ether 1:49) yielding (31% over 4 steps) the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3, 300 K) δ 7.74 (1H, dd, J=8.4 and 2.8 Hz), 7.60 (1H, dd, J=7.3 and 2.5 Hz), 3.95 (3H, s), 2.59 (3H, s).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:36][C:37]4[CH:38]=[CH:39][CH:40]=[C:41]5[C:45]=4[C:44](=[O:46])[NH:43][CH2:42]5)[C:20]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)=[C:12]([O:47][CH3:48])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:3].[OH-].[K+]>O1CCOCC1>[CH3:3][CH:2]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:36][C:37]4[CH:38]=[CH:39][CH:40]=[C:41]5[C:45]=4[C:44](=[O:46])[NH:43][CH2:42]5)[N:18]=3)=[C:12]([O:47][CH3:48])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:1]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cccc3c2C(=O)NC3)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cccc3c2C(=O)NC3)c2ccnc-2[nH]1
Temperature: 120 °C
Yield: 65 %

Procedure:
To a solution of 7-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-dihydro-1H-isoindol-1-one (140 mg, 0.210 mmol) in 1,4-dioxane (8 mL) was added 1.0M potassium hydroxide (6.30 mL, 6.30 mmol) and the resulting reaction was heated in a microwave reactor at 120° C. for 20 min. The reaction was washed with brine (5 ml), organic layer diluted with ethyl acetate (10 mL), adsorded onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM) to produce 7-[(2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-dihydro-1H-isoindol-1-one (0.070 g, 75%). ESIMS (M+H)+=513. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.42 Hz, 6 H) 2.61 (d, J=9.23 Hz, 4 H) 3.08-3.16 (m, 4 H) 3.81 (s, 3 H) 4.39 (s, 2 H) 6.27 (dd, J=3.41, 1.81 Hz, 1 H) 6.51 (dd, J=8.73, 2.51 Hz, 1 H) 6.64 (d, J=2.61 Hz, 1 H) 6.97 (dd, J=3.41, 2.21 Hz, 1 H) 7.10 (d, J=7.62 Hz, 1 H) 7.43-7.50 (m, 1 H) 7.53 (s, 1 H) 7.83 (d, J=8.83 Hz, 1 H) 8.69 (d, J=8.23 Hz, 2 H) 8.79 (s, 1 H) 10.45 (s, 1 H) 11.33 (s, 1 H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[C:30]([NH2:39])(=[O:38])[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[C:30](=[O:38])[NH2:39])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4]
Reactant: NC(=O)c1ccccc1O
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
200 mg of t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 2.0 ml of 1-methyl-2-pyrrolidone, and 85 mg of salicylamide and 129 mg of potassium carbonate were added thereto. The mixture was stirred at 100° C. for 2 hours. After the reaction mixture had been cooled to room temperature, 5.0 ml of water was added thereto. After the mixture had been stirred at room temperature for 1 hour, the white precipitate was collected by filtration. The resulting white solid was washed with water and ether to give of 221 mg of the title compound (89%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:43])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=3)[C:20]([O:31][CH2:32][CH2:33][OH:34])=[C:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH3:42])[CH:36]=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:48]CC1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>C(#N)C.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.CC(O)=O.CCOC(C)=O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[CH:22]=[C:17]([C:16](=[O:43])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:18]=[C:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH3:42])[CH:36]=3)[C:20]=2[O:31][CH2:32][C:33]([OH:48])=[O:34])=[CH:24][C:25]=1[CH3:30]
Reactant: Cc1cc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3ccc(F)c(C)c3)c2OCCO)ccc1F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(=O)NCCCCCCCCc3ccccc3)cc(-c3ccc(F)c(C)c3)c2OCC(=O)O)ccc1F
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of N-8-phenyloctyl-3,5-bis-(4-fluoro-3-methylphenyl)-4-(2-hydroxyethoxy)benzamide (320 mg, 0.546 mmol) in 5 mL acetonitrile at room temperature was added NMMO (162 mg, 1.2 mmol) and TPAP (38.3 mg, 0.109 mmol). The reaction was stirred for 2 hours then additional TPAP (38.3 mg, 0.109 mmol) was added. The reaction was stirred overnight and an additional amount of NMMO (14.7 mg, 0.109 mmol) and TPAP (19 mg, 0.546 mmol) were added. The reaction was then stirred for three more hours and aqueous sodium metabisulfite/sodium dithionite was added. The reaction was then allowed to stir for 1 hour. Then 1N HCl was added. The aqueous solution was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4 and the solvent was removed under vacuum to give a black oil which was subjected to flash column chromatography (20% EtOAc: 80% Hexanes acidified with AcOH) on silica gel that was pretreated with AcOH. There yielded 120 mg, 36.6% of the acid as a yellow oil. 1H NMR (DMSO-d6) δ 1.22–1.27 (m, 4H); 1.53 (quintet, J=6.59 Hz, 4H); 2.27–2.28 (m, 6H); 2.52 (t, J=7.69 Hz, 2H); 3.23 (quartet, J=6.59 Hz, 2H); 3.82 (s, 2H); 7.11–7.25 (m, 7H); 7.41–7.45 (m, 2H); 7.52 (dd, J=7.58 Hz, 1.87 Hz, 2H); 7.80 (s, 2H); 8.49 (t, J=5.60 Hz, 1H); 12.57 (bs, 1H); IR 3375, 2915, 2835, 1630, 1540, 1500, 1450, 1230, 1120, and 970 cm−1; mass spectrum [(−)ESI], m/z 598 [M−H]−; Anal Calcd for C37H39F2NO4.0.17C6H12.0.2C4H8O2.0.88C2H3O2: C, 71.16; H, 6.84; N, 2.04. Found: C, 69.55; H, 6.65; N, 2.09.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)butanoic acid (7.0 g, 34.5 mmol) and K2CO3 (9.5 g, 68.9 mmol) in acetone (70 mL) was added MeI (7.5 g, 51.8 mmol) at rt. The reaction solution was stirred at 45° C. for 12 hrs. The mixture was washed with water and saturated sodium chloride, dried over Na2SO4, and concentrated to afford methyl 4-(tert-butoxycarbonylamino)butanoate (6.2 g, 83%) as a yellow oil. ESI-MS (EI+, m/z): 240 [M+Na]+.
Reaction SMILES: Br.[NH:2]([C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[C:3]([NH2:5])=[NH:4].C(N(CC)CC)C.[C:24]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH:29]([C:34](=O)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:28]1)(=[O:26])[CH3:25].N(C1N=C(C2C=CC=CC=2)SC=1)C(N)=N>CC(C)=O>[C:24]([N:27]1[CH2:28][C:29]2[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:4][C:3]([NH:2][C:6]3[S:7][CH:8]=[C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:10]=3)=[N:5][C:30]=2[CH2:31][CH2:32]1)(=[O:26])[CH3:25]
Reactant: N=C(N)Nc1nc(-c2ccccc2)cs1
Reactant: CC(=O)N1CCC(=O)C(C(=O)c2ccccc2)C1
Agent: Br
Agent: N=C(N)Nc1csc(-c2ccccc2)n1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2nc(Nc3nc(-c4ccccc4)cs3)nc(-c3ccccc3)c2C1
Yield: 26.6 %

Procedure:
To 2-guanidino-4-phenylthiazole hydrobromide (13.14 g, 0.044 mol) was added acetone (240 mL), with stirring. Triethylamine (4.45 g, 6.3 mL, 0.044 mol) was added. The resulting solution was heterogeneous. N-Acetyl-3-benzoyl-4-piperidone (7.18 g, 0.029 mol) was dissolved in acetone (30 mL), with gentle warming, then added to the guanidino phenylthiazole solution. The reaction mixture was heated at reflux for three days. The solid which had precipitated was filtered in a sintered glass funnel, and washed with water to remove triethylamine hydrobromide. The remaining solid, composed of the desired product along with a small amount of the excess starting guanidino phenylthiazole, was recrystallized from methanol to give 3.29 g (7.7 mmol) of the title compound as a tan solid; mp 130°-132° C. A second crop precipitated from the mother liquor and was recrystallized from methanol to give an additional 2.7 g (6.3 mmol). The combined yield was 48%.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5](=[O:21])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:20])[C:16]([O:18]C)=[O:17])=[CH:10][CH:9]=1)[CH3:3].[C-]#N.[Na+]>CN(C)P(N(C)C)(N(C)C)=O.[Cl-].[NH4+]>[CH3:22][C:2]([CH3:3])([O:4][C:5](=[O:21])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH3:20])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)[CH3:1]
Reactant: COC(=O)C(C)Cc1ccc(OCC(=O)OC(C)(C)C)cc1
Agent: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(Cc1ccc(OCC(=O)OC(C)(C)C)cc1)C(=O)O
Temperature: 70 °C
Yield: 11.4 %

Procedure:
Dissolve 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]oxy]-alpha-methyl-benzenepropanoic acid, methyl ester (10 g, 32.4 mmol) in anhydrous hexamethylphosphoramide (160 mL) and treat with sodium cyanide (1.59 g, 32.4 mmol). Heat at 70° C. for 48 hours, cool and dilute with saturated ammonium chloride (300 mL). Extract with ethyl ether (400 mL), wash with water (2×300 mL), then brine (300 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography (5→10% methanol/chloroform) to give the title compound (1.09 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:11]([O-])=[O:12].[Na+]>Cl.O>[N:11]([N:4]1[CH2:3][CH2:2][O:1][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]1=2)=[O:12]
Reactant: c1ccc2c(c1)NCCO2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCOc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 77.4 %

Procedure:
3,4-Dihydro-2H-benzo[1,4]oxazine (425 mg, 3.148 mmol) was dissolved in HCl (3N) at 0° C., and stirred for 5 min. at 0° C. A solution of sodium nitrite (217 mg, 3.148 mmol) in water was added at the same temperature, and the reaction mixture stirred at 0° C. for 1 h. After completion of reaction, water was added and the mixture extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, to give 400 mg desired product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=O)=[CH:4][N:3]=1.O.[NH2:20][NH2:21].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]2[NH:20][N:21]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: NN
Reactant: CSc1nccc(C(=O)c2cnc(Cl)nc2Cl)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Temperature: 50 °C

Procedure:
To a solution of (2,4-dichloro-pyrimidin-5-yl)-(2-methylsulfanyl-pyrimidin-4-yl)-methanone (9.52 g, 31.6 mmol) in THF (100 mL) was added hydrazine hydrate (2.3 g, 46 mmol) and DIPEA (5.9 g, 45.7 mmol). The mixture was heated at 50° C. for 4 hours, then concentrated to dryness. The resulting precipitate was collected by filtration and washed with water to give 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine as a yellow solid. (Yield 7.8 g, 88%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[C@@H](C1C=C2C(C=NN2CC2C=CC=CC=2)=CC=1)COS(C)(=O)=O)(=O)=O.C(N1C2C(=CC([F:80])=CC=2)CC1=O)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:80])=[CH:14][CH:15]=2)[C@:10]2([CH2:18][C@H:17]2[C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:21][CH:20]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Reactant: O=C1Cc2cc(F)ccc2N1Cc1ccccc1
Agent: CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)c1ccc2cnn(Cc3ccccc3)c2c1
Product: O=C1N(Cc2ccccc2)c2ccc(F)cc2[C@]12C[C@H]2c1ccc2cnn(Cc3ccccc3)c2c1
Yield: 63 %

Procedure:
The title compound was prepared in a manner similar to the method of (1R,2S)-1′-benzyl-2-(1-benzyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one using (S)-1-(1-benzyl-1H-indazol-6-yl)ethane-1,2-diyl dimethanesulfonate (501.4 mg, 1.181 mmol) and 1-benzyl-5-fluoroindolin-2-one (285.0 mg, 1.181 mmol). Purification using Biotage Isolera (SNAP 25 g column, 25-100% EtOAc in hexane) yielded the title compound as a cream solid (352 mg, 63%; 97% ee) with the major (1R,2S) enantiomer eluting at 7.03 min (Phenomenex Lux 5μ Cellulose-1 (150×4.6 mm), 1.0 mL/min isocratic at 80% EtOH in hexane for 1.0 min, then gradient 80-90% EtOH in hexane over 10 min). From the racemic reference standard, the retention time of the (1S,2R) enantiomer was 5.95 min using this method. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.40-7.27 (m, 8H), 7.17 (s, 1H), 7.11 (d, J=7.2 Hz, 2H), 6.92 (d, J=8.4 Hz, 1H), 6.67-6.62 (m, 2H), 5.62 (d, J=15.6 Hz, 1H), 5.55 (d, J=15.6 Hz, 1H), 5.51 (t, J=6.0 Hz, 1H), 5.10 (d, J=15.6 Hz, 1H), 4.94 (d, J=16.0 Hz, 1H), 3.53 (t, J=8.4 Hz, 1H), 2.32 (dd, J=9.2, 4.4 Hz, 1H), 2.02 (dd, J=8.0, 3.2 Hz, 1H), MS ESI 474.3 [M+H]+, calcd for [C31H24FN3O+H]+ 474.2.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=[O:16])[CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.N[CH:19](C(=O)C1CCOC1)[C:20](OCC)=O.O1CCC(C(Cl)=O)CC1.C(OCC)(OCC)(OCC)C>CO>[CH3:19][C:20]1[O:16][C:9]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=1
Reactant: CCOC(=O)C(N)C(=O)C1CCOCC1
Reactant: CCOC(=O)C(N)C(=O)C1CCOC1
Agent: CCOC(C)(OCC)OCC
Agent: Cl
Agent: O=C(Cl)C1CCOCC1
Solvent: CO
Product: CCOC(=O)c1nc(C)oc1C1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ethyl 2-amino-3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate, hydrochloride salt [C61, which may be prepared according to the general procedure for synthesis of ethyl 2-amino-3-oxo-3-(tetrahydrofuran-3-yl)propanoate, hydrochloride salt (C11) in Example 3, through the use of tetrahydro-2H-pyran-4-carbonyl chloride in place of tetrahydrofuran-3-carbonyl chloride] (200 g, ≦0.56 mol) was combined with triethyl orthoacetate (200 mL, 1.1 mol) in methanol (200 mL), and the reaction was stirred at room temperature for 2 days. Concentration in vacuo afforded the crude intermediate, ethyl 2-methyl-5-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole-4-carboxylate (C62). This was mixed with acetic acid (500 mL), treated with ammonium acetate (600 g, 7.8 mol) and heated to 99° C. for 2 days. At this point, additional ammonium acetate (100 g, 1.3 mol) was added, and heating was continued for 24 hours. The reaction mixture was then diluted with ethyl acetate (4 L) and water (2 L), and the pH was adjusted to ˜9 with aqueous ammonium hydroxide solution. The aqueous layer was extracted with ethyl acetate (1 L), and the combined organic layers were diluted with cyclohexane (1 L), washed with saturated aqueous potassium bicarbonate solution (1 L), washed with saturated aqueous sodium chloride solution (1 L), and concentrated under reduced pressure. The residue was dissolved in diethyl ether (1 L) and seeded; the resulting crystals were isolated by filtration, affording the product as a solid. Yield: 75 g, 0.31 mol, 55% from tetrahydro-2H-pyran-4-carboxylic acid.