Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16](C2OC3(C)C(C)(C3)O2)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)=[CH:15][N:14]=1
Reactant: Brc1cnc2ncccc2c1
Reactant: CC12CC1(C)OC(c1cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c1)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1cc(-c2cnc3ncccc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
(Some starting materials may be obtained from Princeton Biomolecular Research, Inc., Monmouth Junction, N.J.) To a 50 mL round-bottomed flask was added 3-bromo-1,8-naphthyridine (73 mg, 351 μmol), N-(2-chloro-5-(1,5-dimethyl-2,4-dioxa-bicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (140 mg, 351 μmol), tetrakis(triphenylphosphine)palladium (41 mg, 35 μmol), sodium carbonate (351 μl, 702 μmol), dioxane (3 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (1 mL) and extracted with CH2Cl2 (5×20 mL). The organic extract was washed with saturated NaCl (2 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2 to give N-(2-chloro-5-(1,8-naphthyridin-3-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (98 mg, 67% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C19H12ClFN4O2S: 414.0; found 415.0. 1H NMR (300 MHz, MeOD) δ ppm 7.30 (t, J=8.77 Hz, 2 H) 7.76 (dd, J=8.18, 4.38 Hz, 1 H) 7.89 (dd, J=8.99, 5.04 Hz, 2 H) 8.44 (d, J=2.34 Hz, 1 H) 8.62 (dd, J=8.18, 1.90 Hz, 1 H) 8.70 (d, J=2.34 Hz, 1 H) 8.79 (d, J=2.48 Hz, 1 H) 9.15 (dd, J=4.38, 1.90 Hz, 1 H) 9.39 (d, J=2.48 Hz, 1 H)
Reaction SMILES: C(OC([NH:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][N:11]([C:16]1[CH:25]=[C:24]3[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]3[CH:26]3[CH2:28][CH2:27]3)=[CH:18][C:17]=1[F:33])[CH2:10]2)=O)(C)(C)C.[ClH:34]>>[ClH:34].[NH2:8][C:9]12[CH2:15][CH:14]1[CH2:13][CH2:12][N:11]([C:16]1[CH:25]=[C:24]3[C:19]([C:20](=[O:32])[C:21]([C:29]([OH:31])=[O:30])=[CH:22][N:23]3[CH:26]3[CH2:27][CH2:28]3)=[CH:18][C:17]=1[F:33])[CH2:10]2
Reactant: CC(C)(C)OC(=O)NC12CC1CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Agent: Cl
Product: NC12CC1CCN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 62 %

Procedure:
According to the procedure of Example 34B, the compound of Step A (287.2 mg, 0.63 mmol) was converted with hydrochloric acid to provide the title compound, mp 235° C. (152.4 mg, 0.387 mmol, 62% yield).
Reaction SMILES: C(OC(=O)[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)(C)C.C(OC(=O)N(CC1C=CC(Cl)=CC=1)C1C=CC(C=O)=CN=1)(C)(C)C.[N:52]1([CH2:58][CH2:59][O:60][C:61]2[CH:62]=[C:63]3[CH:69]=[CH:68][NH:67][C:64]3=[N:65][CH:66]=2)[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.N1C2C(=CC=CC=2)C=N1.COC1C=C2C(=NC=1)NC=C2.ClC1C=C2C(=NC=1)NC=C2>>[N:52]1([CH2:58][CH2:59][O:60][C:61]2[CH:62]=[C:63]3[C:69]([CH2:25][C:22]4[CH:23]=[CH:24][C:19]([NH:7][CH2:8][C:9]5[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=5)=[N:20][CH:21]=4)=[CH:68][NH:67][C:64]3=[N:65][CH:66]=2)[CH2:53][CH2:54][O:55][CH2:56][CH2:57]1
Reactant: c1cc2cc(OCCN3CCOCC3)cnc2[nH]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C=O)cn1
Agent: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)c1ccc(C=O)cn1
Agent: COc1cnc2[nH]ccc2c1
Agent: Clc1cnc2[nH]ccc2c1
Product: FC(F)(F)c1ccc(CNc2ccc(Cc3c[nH]c4ncc(OCCN5CCOCC5)cc34)cn2)cc1

Procedure:
Additional compounds may be prepared using steps 3 and 4 of Scheme 32, using (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester 19 or replacing it with (5-Formyl-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester (43, prepared as described in Example 17) and replacing 5-(2-Morpholin-4-yl-ethoxy)-1H-pyrrolo[2,3-b]pyridine 79 with an appropriate azaindole, prepared as in Example 29 or 5-methoxy-7-azaindole (prepared as described in Example 31) or with commercially available 5-chloro-7-azaindole. The following compounds were made following this procedure:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=3)=[O:24])[CH:19]=[CH:18][C:17]=2[F:32])([CH2:14][F:15])[N:13]=1)(C)(C)C.Cl.O1CCOCC1.Cl.CO>C(Cl)Cl>[ClH:31].[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:16]2[CH:21]=[C:20]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=3)=[O:24])[CH:19]=[CH:18][C:17]=2[F:32])([CH2:14][F:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)COC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: NC1=N[C@](CF)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)COC1

Procedure:
A solution of ((R)-5-{5-[(5-chloro-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (106 mg, 0.22 mmol), 4 N HCl/Dioxan (1.1 ml, 4.41 mmol) and 3 N HCl/MeOH in CH2Cl2 was stirred for 15 h at room temperature and for 2 h at 40° C. to complete the conversion. The yellow solution was evaporated and taken up in MeOH. TBME was added and the white precipitate was filtered off to provide the title compound.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH3:3].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.Cl>C(O)C>[O:16]=[C:17]1[NH:9][C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:2][CH3:3])=[N:8][CH:24]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccccc1C(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2ccccc2OCC)[nH]c1=O
Temperature: 0 °C

Procedure:
To a cooled solution of sodium (1.04 g., 0.045 g-atom) in 35 ml. of ethanol was added all at once 2-ethoxybenzamidine (7.4 g., 45 mmole). There was then added to this suspension over a 5 minute period a solution of diethyl ethoxymethylenemalonate (9.7 g., 45 mmole) in 20 ml. of ethanol whereupon a pale yellow precipitate soon formed. An additional 25 ml. of ethanol was added to the reaction mixture which was then heated under reflux for 21/4 hours. The cooled solution was poured into about 500 ml. of ice-water and acidified with 6N HCl to produce a pale yellow solid. The solid was dried to give 10.2 g., m.p. 144°-149°, of title product. Recrystallization from acetonitrile gave 9.8 g., m.p. 147°-150°, of purified product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](C(=O)C)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].NC1C=CC([CH2:21][C@@H:22]([OH:24])[CH3:23])=CC=1>>[N+:11]([C:3]1[CH:2]=[CH:7][C:6]([CH2:21][C@@H:22]([OH:24])[CH3:23])=[CH:5][CH:4]=1)([O-:13])=[O:12]
Reactant: C[C@H](O)Cc1ccc(N)cc1
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: C[C@H](O)Cc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(4-chloro-3-nitrophenyl)ethanone and (2S)-1-(4-aminophenyl)-2-propanol (step 2).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)=[N:4][N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([CH2:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:33]=4)[CH2:29][CH2:30]3)=[N:3][N:4]=2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc2c(-c3ccc(OC)c(OC)c3)nnc(Cl)c2c1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: COc1ccc2c(-c3ccc(OC)c(OC)c3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-(3,4-dimethoxyphenyl)-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(Cl)CCl>[Cl:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([NH:17][CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=C(O)c1ccc2nc(Cl)sc2c1
Reactant: NC1CC1
Solvent: ClCCCl
Product: O=C(NC1CC1)c1ccc2nc(Cl)sc2c1

Procedure:
2-chloro-N-cyclopropylbenzo[d]thiazole-6-carboxamide was prepared by EDC coupling of 2-chlorobenzo[d]thiazole-6-carboxylic acid and cyclopropylamine.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (22 mg, 0.05 mmol, 1 eq), DIPEA (17 μl, 0.10 mmol, 2 eq) and TBTU (18 mg, 0.055 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 30 min before the addition of 1-amino-4-methylpiperazine (12 μl, 0.1 mmol, 2 eq). The RM was then stirred at rt for 4 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(4-methylpiperazin-1-yl)benzamide (white solid, 8 mg, 30%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])=[O:11])=[CH:8][CH:7]=1)=[O:4].[CH3:23][NH:24][CH3:25]>O1CCCC1>[CH3:23][N:24]([CH2:2][C:3]([NH:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([NH:12][C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:20])=[O:11])=[CH:8][CH:7]=1)=[O:4])[CH3:25]
Reactant: Cc1cccc(C)c1NC(=O)c1ccc(NC(=O)CCl)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=O)c1ccc(NC(=O)CN(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.0 g of 4-[(chloroacetyl)amino]-N-(2,6-dimethylphenyl)benzamide and 22 ml of 40% aqueous dimethylamine in tetrahydrofuran was stirred at room temperature overnight. After the reaction was evaporated to dryness, the residue was taken up in chloroform, washed with 10% aqueous sodium carbonate, water, and a saturated sodium chloride solution, dried over sodium sulfate, and evaporated to dryness. Crystallization from methanol/water provided 2.8 g of the desired title product, m.p. 276°-278° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([OH:20])=O)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.C(N1C=CN=C1)([N:23]1C=CN=C1)=O.[OH-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]([NH2:23])=[O:20])[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)O)c12
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C(N)=O)c12

Procedure:
To a solution of 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (14.0 mg, 0.051 mmol) and 1,1′-carbonyldiimidazole (13.0 mg, 0.077 mmol) in N,N-dimethylformamide (2 ml) was added 28% ammonium hydroxide solution (0.072 ml, 0.51 mmol). After 30 minutes the reaction mixture was purified directly by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.05% TFA to give 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamide as gray solids. 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H); 8.33 (s, 1H); 8.25 (s, 1H); 8.06 (s, 1H); 7.61 (s, 1H); 7.29 (s, 1H); 7.15 (s, 1H); 4.07 (s, 3H); 3.87 (s, 3H). LRMS (ESI) calculated for C13K4N5O2 [M+H]−, 272.1 found 272.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([NH:25][C:26]([NH:28][C:29]3[N:30]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)[N:31]=[C:32]([C:34]([CH2:38][F:39])([CH3:37])[CH2:35][F:36])[CH:33]=3)=[O:27])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:47].O1CCOCC1>ClCCl>[ClH:47].[F:36][CH2:35][C:34]([C:32]1[CH:33]=[C:29]([NH:28][C:26]([NH:25][C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)=[O:27])[N:30]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[N:31]=1)([CH2:38][F:39])[CH3:37]
Reactant: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(CF)CF)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1

Procedure:
Stir 4-(4-{3-[5-(2-fluoro-1-fluoromethyl-1-methyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.1 mmol, 0.6 g) and dissolve in 5 mL of dichloromethane and hydrogen chloride 4.0 M in dioxane (5.3 mmol, 1.3 mL) at room temperature overnight. Concentrate under reduced pressure. Triturate the white solid formed with diethyl ether. LCMS ES+ (m/z) 535 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]([NH:12]C(OC(C)(C)C)=O)[CH2:10][CH2:9][N:8]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[CH2:7]1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]([NH2:12])[CH2:10][CH2:9][N:8]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CN(CCc2ccc(OC)c(OC)c2)CC[C@@H]1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CN(CCc2ccc(OC)c(OC)c2)CC[C@@H]1N
Yield: 48.7 %

Procedure:
A solution of (3R,4R) and (3S,4S)-4-tert-butoxycarbonylamino-1-[2-(3,4-dimethoxy-phenyl)-ethyl]-piperidine-3-carboxylic acid ethyl ester (24 mg) in 1 ml TFA was stirred 1 h at 0° C. The mixture was poured onto NaOH 1M/ice and extracted with AcOEt. The combined organic layers were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an oil which was purified by column chromatography (Isolute SPE Flash NH2 10 g, AcOEt/heptane, 1/2) to give 9 mg (50%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13])#[N:2].Br[CH2:15][C:16](=[O:32])[CH2:17][C@H:18]1[C@H:23]([O:24][CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27]>>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]([CH2:15][C:16](=[O:32])[CH2:17][C@H:18]1[C@H:23]([O:24][CH3:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[C:6]2=[O:13])#[N:2]
Reactant: N#Cc1ccc2nc[nH]c(=O)c2c1
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2ccc(C#N)cc2c1=O
Yield: 49 %

Procedure:
By the method of Example 4, 6-cyanoquinazolin-4(3H)-one and allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxypiperidine-1-carboxylate were converted to title compound in 49% yield; 1H-NMR(CDCl3) 1.2-1.9 (m, 4H), 2.9 (d, 2H), 2.9-3.5 (m, 4H), 4.6-6.2 (m, 5H), 5.2 (s, 2H), 7.8-8.6 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)cn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (200 mg, 0.58 mmol) in DMF (10 mL) and H2O (2 mL) under nitrogen was added 6-methoxypyridin-3-ylboronic acid pinacol ester (202 mg, 0.86 mmol) and potassium carbonate (160 mg, 1.16 mmol). Upon completion of addition, the mixture was degassed with nitrogen for 15 min and then tetrakis(triphenylphosphine)-palladium (66 mg, 0.0050 mmol) was added. The mixture was again degassed with nitrogen for 10 min. After this time, the reaction mixture was heated to 90° C. where it stirred for 12 h. The reaction mixture was then allowed to cool to room temperature and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by flash column chromatography using 16% ethyl acetate in petroleum ether to afford 2-(6-methoxypyridin-3-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (140 mg) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.26 (d, J=2.4 Hz, 1H), 8.70-8.67 (dd, J=8.8, 2.4 Hz, 1H), 8.23-8.22 (d, J=5.2 Hz, 1H), 7.84-7.76 (m, 2H), 7.73-7.69 (dt, J=8.0, 2.0 Hz, 1H), 7.58-7.48 (m, 5H), 7.32-7.30 (d, J=7.6 Hz, 1H), 7.25-7.23 (m, 2H), 6.95-6.93 (d, J=8.8 Hz, 1H), 6.81-6.79 (t, J=4.0 Hz, 1H), 4.72-4.71 (d, J=4.0 Hz, 2H), 3.94 (s, 3H). LCMS Method S: retention time 3.96 min, [M+1]=420.2. HPLC Method B: purity 98.9%, retention time 8.93 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6](Cl)(=[O:9])[CH2:7][CH3:8].[Sn](Cl)(Cl)(Cl)Cl>C1C=CC=CC=1>[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:9])[CH2:7][CH3:8]
Reactant: CCC(=O)Cl
Reactant: c1ccsc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCC(=O)c1cccs1
Reaction time: 3 h
Yield: 71 %

Procedure:
The procedure for the Friedel-Crafts acylation of thiophene with propionyl chloride in the presence of tin tetrachloride is as follows. Tin tetrachloride (630 mg, 2.4 mmol) was added slowly to perfluorohexanes (FC-72, 3 mL) in a test tube (14 mm×105 mm) and then a mixed benzene solution (3 mL) of thiophene (168 mg, 2.0 mmol) and propionyl chloride (185 mg, 2.0 mmol) was slowly poured into the test tube. The tin tetrachloride layer in the bottom was stirred gently so as not to mix the three phases. which disappeared after 3 h. The benzene layer was decanted, washed with 10% HCl and H2O, dried over MgSO4, and concentrated. The residue was purified by short column chromatography (10 mm×40 mm) on silica gel with benzene to give 2-propionylthiophene in 71 % yield (200 mg).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[C:7](=[C:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)([CH3:9])[CH3:8].[I-].C[S+](C)(C)=O>CS(C)=O>[C:7](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]21[O:4][CH2:2]2)([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)=C1CCC(=O)CC1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)=C1CCCCC12CO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Potassium t-butoxide (3.3 g, 29.4 mmol) was added to a mixture of ketone (3, 2.5 g, 18.1 mmol) and trimethylsulfoxonium iodide (6.45 g, 29.4 mmol) in dry dimethyl sulfoxide (40 mL) under nitrogen atmosphere at room temperature. The mixture was stirred for 4.0 h at room temperature. The reaction was quenched by the addition of cold water (40 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layer was washed with water (75 mL) followed by brine (75 mL) and dried over sodium sulfate. The filtered organic layer was concentrated under vacuum to give an oil. Weight: 2.13 g. Weight yield: 77%. 1H-NMR (400 MHz, CDCl3): δ 1.42-1.50 (m, 2H), 1.55-1.61 (m, 2H), 1.65 (s, 6H), 2.31 (t, 4H), 2.61 (s, 2H). MS (APCI method): No molecular ion peak was observed.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(OP([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(OCC)=O)C.C1(C)C=CC=CC=1.C(O)C.[O-]CC.[Na+]>O>[CH2:24]([O:23][C:21](=[O:22])[CH:20]=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH3:25]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
First Step: 200.0 g of 1,4-dioxaspiro[4,5]decan-8-one (10), 301.4 g of ethyl diethylphosphonoacetate and 1,000 mL of toluene were added to a reactor under nitrogen atmosphere, and stirred at 5° C. 457.5 g of a 20% sodium ethoxide ethanol solution was added dropwise thereto at a temperature range of from 5 to 11° C. over 2 hours, followed by further stirring at 10° C. for 3 hours. After confirming that the reaction had been completed by GC analysis, the reaction mixture was poured into and mixed with 2,000 mL of water at 0° C. The mixture was separated into an organic layer and an aqueous layer by standing still, so as to attain extraction to the organic layer. The resulting organic layer was fractionated and washed with water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography using heptane as eluent, followed by distilling the solvent off under reduced pressure, to obtain 267.3 g of (1,4-dioxaspiro[4.5]dec-8-ylidene)acetic acid ethyl ester (11) as a pale yellow liquid.