Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C[Si]([N:53]=[N+:54]=[N-:55])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:53]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:44])([F:45])[F:46])=[CH:39][CH:38]=4)=[CH:33][CH:32]=3)[CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=3)=[CH:47][CH:48]=2)=[N:2][N:55]=[N:54]1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)Cc2ccc(C#N)cc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)Cc2ccc(-c3nnn[nH]3)cc2)cc1
Temperature: 80 °C

Procedure:
A solution of 295 mg (0.53 mmol) of methyl 4-[(4E)-3-(4-cyanobenzyl)-5-(2-{[4′-(trifluoromethyl)biphenyl-4-yl]methoxy}phenyl)pent-4-en-1-yl]benzoate in 20 ml of toluene is mixed with 1.33 ml (9.99 mmol) of trimethylsilyl azide and 249 mg (1 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: dichloromethane→dichloromethane/methanol 10:1). 387 mg (0.56 mmol, 64% of theory) of a white foam are obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:15]S(C(C)(C)C)=O)[CH2:12][CH:13]=[CH2:14])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl>CO>[CH3:3][O:4][C:5]1([O:1][CH3:2])[CH2:10][CH2:9][CH:8]([CH:11]([NH2:15])[CH2:12][CH:13]=[CH2:14])[CH2:7][CH2:6]1
Reactant: C=CCC(NS(=O)C(C)(C)C)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CO
Product: C=CCC(N)C1CCC(OC)(OC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(1-(1,4-dioxaspiro[4.5]decan-8-yl)but-3-en-1-yl)-2-methylpropane-2-sulfinamide (828 mg, 2.63 mmol), prepared in the previous step, was dissolved in methanol (20 mL) and treated with HCl (4.4 mL. 5.5 mmol, 1.25 M in MeOH), stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, triturated with ether, decanting the supernatant several times and the residue dried under high vacuum afford the product as a white foam (HCl salt).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[N:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][NH2:11])[N:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCn1ccc([N+](=O)[O-])n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1ccc([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A solution of 206a (2.0 g, 7.0 mmol) in ethanol (30 mL) was added hydrazine hydrate (1 mL, 21 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was evaporated and the residue was purified by silica-gel eluting with 10:1 methylene chloride/methanol to give 206b as a white solid (0.8 g, 80%). MS: (M+H)+ 157.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[F:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.6 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-fluorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.20 mg, 64.7% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2H), 7.30-7.20 (m, 5H), 7.20 (m, 3H), 6.97 (apparent d, 1H, J=7.7 Hz), 6.87 (m, 1H), 6.76 (m, 1H), 5.26 (apparent dd, 1H, J=4.0, 8.1 Hz), 3.09 (m, 2H), 2.66 (m, 2H), 2.51 (m, 2H), 2.3-2.1 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m/e: 475.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:12][CH:13]=2)[N:8]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[N:7]=1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(C2CCCCO2)c2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(C2CCCCO2)c2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Ethyl6-(tert-butyldiphenylsilyloxy)-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carboxylate (1.299 g) which can be prepared according to the method described in Reference example 19, etc. was dissolved in dehydrated THF (12.3 mL; manufactured by Kanto Chemical Co., Inc.), added with 1 mol/L-TBAF-THF solution (3.69 mL; manufactured by Sigma-Aldrich Co.), followed by stirring for 2 hours at room temperature under nitrogen atmosphere. The reaction solution was added with ethyl acetate, washed three times with brine, and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography “COLUMN-A”; n-hexane:ethyl acetate=100:0→81:19) to obtain the title compound (0.660 g).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([OH:14])=O)[CH2:4]1.[C:15]1([S:21]([NH2:24])(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[N+:9]([O-:11])([O:8][C@H:7]1[CH2:6][C@H:5]([C:12](=[O:14])[NH:24][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH2:4][C@@H:3]1[O:2][CH3:1])=[O:10]
Reactant: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Reactant: NS(=O)(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@H]1C[C@@H](C(=O)NS(=O)(=O)c2ccccc2)C[C@@H]1O[N+](=O)[O-]
Reaction time: 12 h

Procedure:
A mixture of (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylic acid (example 1, 105 mg, 0.510 mmol) and benzenesulfonamide (173 mg, 1.10 mmol) was dissolved in dichloromethane (4 mL). Triethylamine (240 pl, 1.72 mmol) was added, followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (291 mg, 0.765 mmol). The reaction mixture was stirred for 12 hours. Purification of the crude product by reversed-phase mass-directed high-performance liquid chromatography afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 1.93-2.02 (m, 1H), 2.15-2.26 (m, 2 H), 2.34 (dt, J=6.8, 15.7 Hz, 1H), 2.93-3.01 (m, 1H), 3.50 (s, 3H), 3.90-3.94 (m, 1H), 5.33-5.37 (m, 1H), 7.55 (t, J=7.8 Hz, 2H), 7.65 (t,J=7.5 Hz, 1H), 8.03-8.07 (m, 2H), 9.42 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH2:39][CH3:40])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]1[C@@H:9]([NH:16][C:17]([C:19]2[S:20][C:21]([CH2:39][CH3:40])=[C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[C:31]([O:33][CH2:34][C:35]([F:38])([F:37])[F:36])[CH:30]=[N:29][C:28]=34)[CH:23]=2)=[O:18])[C:10]([F:14])([F:15])[CH2:11][CH2:12][CH2:13]1
Reactant: CCc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OCC(F)(F)F)cnc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnn2cc(OCC(F)(F)F)cnc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
tert-Butyl{(1R,2R)-2-[({5-ethyl-4-[6-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]thiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamate (34.0 mg, 0.056 mmol) was dissolved in dichloromethane (1.0 mL) and trifluoroacetic acid (0.100 mL, 1.30 mmol) was added. The reaction was stirred at 40° C. for 2 h. The reaction mixture was quenched with 1N KOH in MeOH and concentrated under reduced pressure. The residue was mixed with water and extracted 3× with dichloromethane. The organic layers were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (0-20% MeOH/DCM) to give the title compound (23.0 mg, 0.046 mmol). LRMS (APCI) calc'd for (C21H22F5N5O2S) [M+H]+, 504.1; found 504.0. 1H NMR (CDCl3, 500 MHz) δ 8.48 (s, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.03 (s, 1H), 4.52 (m, 1H), 4.43 (d, J=7.8, 2H), 3.36 (s, 1H), 2.96 (q, J=7.2, 2H), 2.17 (s, 1H), 1.48-2.02 (m, 5H), 1.33 (t, J=7.3, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH2:21][NH:20][CH2:19][CH2:18][C:11]=3[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[N:14]=2)=[CH:5][CH:4]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:20]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([NH:15][CH2:16][CH3:17])[N:14]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=3)[C:10]=2[CH2:21]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCNc1nc2c(c(-c3ccc(Cl)cc3)n1)CNCC2
Reactant: BrCc1ccccc1
Agent: Cl
Product: CCNc1nc2c(c(-c3ccc(Cl)cc3)n1)CN(Cc1ccccc1)CC2
Yield: 27.2 %

Procedure:
The title compound was prepared as described in Example 5 starting with 4-(4-chlorophenyl)-2-ethylamino- 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride (1.1 g, 3.4 mmol) and benzyl bromide (0.4 mL, 3.4 mmol) to produce 0.35 g (27%) of 6-benzyl-4-(4- chlorophenyl)-2-ethylamino-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. m.p. 138°-141° C. MS: 379 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][C:27]=1[C:28](O)=[O:29]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:28]([C:27]4[CH:26]=[C:25]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:24][C:23]=4[CH3:22])=[O:29])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)O
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(-c3ccccc3)oc2C)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 2-methyl-5-phenyl-3-furoic acid (76.4 mg, 0.378 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue was dissolved in methanol, filtered through an SCX SPE and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-methyl-5-phenyl-3-furamide (24 mg, 28%). NMR; δH CDCl3 7.81,(2H, d), 7.64,(2H, d), 7.55-7.53,(2H, m), 7.45,(1H, s), 7.40-7.37,(4H, m), 7.30-7.25,(2H, m), 6.78,(1H, s), 6.26,(1H, t), 3.33,(2H, t), 2.70,(3H, s), 2.22,(3H, s), 1.07,(1H, m), 0.57,(2H, m), 0.28,(2H, m). LCMS: retention time 3.93 min, MH+465.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:28][S:29]([O:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:16])=[O:17])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:31])=[O:30]
Reactant: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)cn2)cc1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)cn2)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of ethyl 2-[(2-hydroxy-4-{[5-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)-hydrazono]propanoate (37.7 g) in pyridine (450 mL) was added methanesulfonyl chloride (8.9 mL) at 0° C., and the mixture was stirred at room temperature for 1 h. Methanesulfonyl chloride (8.9 mL) was added to the mixture at 0° C. again, and the mixture was stirred at room temperature for 1 h. Furthermore, methanesulfonyl chloride (8.9 mL) was added to the mixture at 0° C., and the mixture was stirred at room temperature for 15 h. The mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed successively with 1M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (37.05 g, 83%) as an off-white solid. MS 472 (MH+).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36](C(OC(C)(C)C)=O)[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:44]([O:46]CC)=[CH2:45].[ClH:59]>O1CCOCC1.O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[NH:36][CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:44](=[O:46])[CH3:45].[ClH:59]
Reactant: C=C(OCC)c1c(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1c(C2CC3CCC(C2)N3)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.1 g, 1.3 mmol) in dioxane (7 mL) was added 4 M HCl in water (2.6 ml) at 0° C. After stirring for 10 min at 0° C., 4 M HCl in dioxane (2.6 mL) was added. The reaction mixture was stirred at 0° C. for 30 min and the cooling bath was removed to warm it up to room temperature for 15 h, at which time LC/MS analysis confirmed full consumption of starting material. The solvent was removed in vacuo to get the desired product as an HCl salt.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].CN(C)C=O.[H-].[Na+].Cl[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39][N:38]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:37]4[CH:42]=[C:41]([CH3:43])[N:40]=[CH:39][N:38]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Cc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cc(C)ncn2)C3)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0499 g, 0.000130 mol) in dry N,N-Dimethylformamide (1.00 mL, 0.0129 mol) was cooled at 0° C. then added sodium hydride, 60% dispension in mineral oil (3:2, Sodium hydride:Mineral Oil, 0.0109 g), warmed to room temperature, stirred for 10 minutes, added 4-Chloro-6-methylpyrimidine (0.0196 g, 0.000152 mol) heated at 60° C. for 3 hours. LC-MS does show some product present but a lot of starting material is still remaining. The reaction mixture was heated at 60° C. and stirred overnight. The reaction mixture was filtered and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.44 (s, 1H), 8.21 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.86 (s, 1H), 6.16 (t, J=5.6, 1H), 4.69 (s, 2H), 3.87 (s, 2H), 3.79-3.68 (m, 4H), 3.48 (d, J=4.4, 4H), 3.20-3.05 (m, 2H), 2.75 (s, 2H), 2.30 (s, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+475.3 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[CH:9][CH:8]=[C:7]([Br:27])[CH:6]=2.[C:28](OCC)(OCC)(OCC)[CH2:29][CH3:30]>>[Br:27][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:12]([CH2:13][CH:14]4[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]4)[C:28]([CH2:29][CH3:30])=[N:1][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2c(N)cnc3cc(Br)ccc23)CC1
Reactant: CCOC(CC)(OCC)OCC
Product: CCc1nc2cnc3cc(Br)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77.1 %

Procedure:
The method described in Part A of Examples 142-144 was used to treat tert-butyl 4-[(3-amino-7-bromoquinolin-4-ylamino)methyl]piperidine-1-carboxylate (15.0 g, 34.5 mmol) with triethyl orthopropionate (6.68 g, 37.9 mmol). After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 95:5 chloroform:CMA) followed by recrystallization from ethyl acetate to provide 12.6 g of tert-butyl 4-[(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate as a white powder, mp 208-209° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:8][CH2:7][CH2:6][O:5]1.[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:27])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[C:12]([F:30])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:9][C:10]1[CH:29]=[CH:28][C:13]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH2:2][CH2:3][CH:4]4[O:8][CH2:7][CH2:6][O:5]4)=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][N:16]=2)=[C:12]([F:30])[CH:11]=1
Reactant: BrCCC1OCCO1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCC1OCCO1
Temperature: 100 °C
Yield: 16.6 %

Procedure:
A solution of 2-(2-bromoethyl)-1,3-dioxolane (258 mg, 1.4 mmol) in DMF (0.5 ml) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (329 mg, 1.02 mmol) and potassium carbonate (264 mg, 2 mmol) in DMF t2 ml). The mixture was heated at 100° C. for 3 hours and allowed to cool. The volatiles were removed by evaporation, and the residue partitioned between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic phase was separated and passed through phase separating paper. The solvent was removed by evaporation, and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 4-(4-chloro-2-fluoroanilino)-7-(2-(1,3-dioxolan-2-yl)ethoxy)6-methoxyquinazoline (71 mg, 17%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][CH2:7][C:6]=2[CH:13]=1.C([Li])CCC.CN(OC)[C:21](=[O:23])[CH3:22]>C1COCC1.C(OCC)(=O)C>[C:21]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[O:8][CH2:7][C:6]=2[CH:13]=1)(=[O:23])[CH3:22]
Reactant: CON(C)C(C)=O
Reactant: CC1(C)OCc2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)COC(C)(C)O2
Reaction time: 0.5 h

Procedure:
To the product of step (a) (110 g, 0.46 mol) in 1.0 L of THF at −78° C. was added 236 mL (0.51 mol) of 2.14 M n-butyllithium in hexanes via a dropping funnel. After 30 minutes, N-methyl-N-methoxy acetamide (71 g, 0.69 mol, available from TCI) was added. After 2 hours, the reaction mixture was quenched with water, diluted with 2.0 L of 1.0 M aqueous phosphate buffer (pH=7.0) and extracted once with diethyl ether. The diethyl ether phase was washed once with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a light orange oil. The oil was dissolved in a minimum volume of ethyl acetate, diluted with hexanes, and to give the title compound as a crystalline solid.
Reaction SMILES: C[O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Br.[CH3:9][O:10][C:11]1[CH:55]=[C:54]([O:56][CH3:57])[CH:53]=[C:52]([O:58][CH3:59])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:45]([O:46][CH3:47])=[CH:44][C:43]([O:48][CH3:49])=[CH:42][C:41]=1[O:50][CH3:51])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH2:37])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=1>>[CH3:59][O:58][C:52]1[CH:53]=[C:54]([O:56][CH3:57])[CH:55]=[C:11]([O:10][CH3:9])[C:12]=1/[CH:13]=[CH:14]/[CH:15]([S:25]([CH:28](/[CH:38]=[CH:39]/[C:40]1[C:41]([O:50][CH3:51])=[CH:42][C:43]([O:48][CH3:49])=[CH:44][C:45]=1[O:46][CH3:47])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([NH:37][CH2:6][CH2:5][CH2:4][C:3]([OH:8])=[O:2])[CH:30]=1)(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:8])[CH:17]=1
Reactant: COC(=O)CCCBr
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NCCCC(=O)O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NCCCC(=O)O)c2)c(OC)c1

Procedure:
A solution of methyl-4-bromobutyrate (40 mmol) and (E)-2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method B. The product obtained was purified by recrystallization from acetone. (m.p. 86-88° C.)
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([O:16]C)=O)[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:18]>CO>[C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:14]([NH2:18])=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc2oc(C(C)(C)C)nc12
Reactant: N
Solvent: CO
Product: CC(C)(C)c1nc2c(C(N)=O)cccc2o1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Methyl 2-t-butyl-4-benzoxazole carboxylate (0.1 g; 0.46mmol) was dissolved in methanol (5 ml), and to this was added aqueous ammonia (5 ml). The mixture was warmed to 40° C. and left to stir for 6 hours at ambient temperature. Once the reaction was complete the solvent was removed under reduced pressure and the product was recrystallised from boiling ethyl acetate and petrol (73%).