Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](OC)(=[O:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]>O1CCCC1>[CH2:7]([OH:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCC=CCCCCCCCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC=CCCCCCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a dry 2 L 3-neck round bottom flask fitted with a nitrogen inlet and outlet, thermocouple, condenser, mechanical stirrer and pressure-equalizing dropping funnel was added lithium aluminum hydride (30.10 g, 0.754 mol, 95% technical grade solid) in one portion, under a positive pressure of nitrogen. The metal hydride was suspended in anhydrous tetrahydrofuran (500 mL) and the mixture cooled on an ice bath. Methyl 9-dodecenoate (200 g, 0.942 mol) was added dropwise via addition funnel to the stirred lithium aluminum hydride suspension over 1 h at such a rate as to maintain the internal temperature below 50° C. When the reaction exotherm subsided, the external cooling bath was removed and the resulting viscous mixture was stirred for a further 8 h at ambient temperature. Complete consumption of starting material was confirmed by thin layer chromatography and by FTIR. The reaction was quenched by the careful addition of the reactor contents to a 4 L Erlenmeyer flask containing chilled concentrated aqueous sodium chloride (300 mL). The reactor was rinsed with ethyl acetate (100 mL) then 10% (v/v) aqueous sulfuric acid (100 mL); both rinse aliquots were combined with the reaction neutralization mixture. An additional aliquot of 10% (v/v) aqueous sulfuric acid was added to neutralize the aqueous phase then the biphasic neutralization mixture was transferred to a separatory funnel. The aqueous phase was partitioned and washed with ethyl acetate (100 mL×2). The combined organic phases were successively washed with concentrated aqueous sodium bicarbonate (100 mL), brine (100 mL), dried (MgSO4) then filtered. The organic phase was concentrated in vacuo, giving 9-dodecen-1-ol (165 g, 95%) as clear, colorless oil.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:38])[NH:15][C:16](=[O:37])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH:30]=[CH:29][CH:28]=4)[CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:37])[NH:15][C:14]2=[O:38])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(-c3cccc4ccccc34)cc12
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccc(-c3cccc4ccccc34)cc12

Procedure:
3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-1-naphthyl-1H-indol-3-yl)pyrrole-2,5-dione, prepared as in Example 31, was reduced with Mg in methanol as described in Example 2, Procedure C, to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-(1-naphthyl)-1H-indol-3-yl)pyrrolidine-2,5-dione. 1H NMR (CD3OD) δ: 1.85-1.95 (m, 1H), 1.95-2.05 (m, 1H), 2.74-2.88 (m, 2H), 3.72-3.83 (m, 1H), 3.88-3.98 (m, 1H), 4.40 (d, J=6.4 Hz, 1H), 4.62 (d, J=6.4 Hz, 1H), 6.80 (d, J=6.8 Hz, 1H), 6.78 (t, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.07-7.13 (m, 2H), 7.18-7.23 (dd, J=8.4 Hz, J=1.6 Hz, 2H), 7.27-7.34 (m, 2H), 7.41-7.49 (m, 3H), 7.78-7.83 (dd, J=8.4 Hz, J=3.2 Hz, 2H), 7.86-7.90 (d, J=7.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[O:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5](=[CH:12][CH:13]=1)[C:6]([O:7][CH3:8])=[O:11]
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(F)cc1N

Procedure:
A mixture of 7-fluoro-1H-3,1-benzoxazine-2,4-dione (13.5 g) and sodium methoxide (0.2 g) in methanol (30 ml), was heated on a steam bath until vigorous bubbling ceased. It was then heated under reflux for 31/2 hours, cooled, added to aqueous sodium bicarbonate (10%; 300 ml) and extracted with ethyl acetate. The extract was washed with water dried and evaporated to give methyl 4-fluoroanthranilate, mp 68°-70°. (Compound 8).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH3:25])=[O:5])C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:4](=[O:5])[C:6]3[CH:7]=[N:8][C:9]4[C:10]([O:24][CH3:25])=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[N:16]([CH:17]3[CH2:18][CH2:19][CH:20]([CH3:23])[CH2:21][CH2:22]3)[C:34]2=[O:35])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCC(C)CC1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(Cl)cc3)c(=O)n(C3CCC(C)CC3)c12
Yield: 74.5 %

Procedure:
3-(4-Chloro-phenyl)-7-methoxy-1-(4-methyl-cyclohexyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (55 mg) was prepared from 8-methoxy-4-(4-methyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (0.164 mmol) and 1-chloro-4-isocyanato-benzene (0.25 mmol) following general procedure C. LCMS: m/z 450 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]3=[O:28])[N:13]=2)=[N:6][CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][C:16]3=[O:28])[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2csc(Nc3ncc(Br)cc3Oc3ccc(F)cc3)n2)C(=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C1CNCCN1Cc1csc(Nc2ncc(Br)cc2Oc2ccc(F)cc2)n1
Reaction time: 2 h
Yield: 71.7 %

Procedure:
In a 20 mL scintillation vial equipped with magnetic stirrer tert-butyl 4-((2-(5-bromo-3-(4-fluorophenoxy)pyridin-2-ylamino)thiazol-4-yl)methyl)-3-oxopiperazine-1-carboxylate (0.020 g, 0.035 mmol) was dissolved in 1 ml of CH2Cl2 and 4M HCl in dioxane (0.50 mL, 2.0 mmol) was added. The resulting mixture was agitated for 2 hours, diluted with 5 mL of ether and the solvent was decanted off. The residue was dried to provide the title compound (0.012 g, 73% yield). 1H NMR (d6-DMSO)S 3.25-3.78 (m, 6H), 6.99 (s, 1H), 7.28-7.36 (m, 4H), 8.23 (s, 1H), 8.34 (s, 1H), 10.24 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:28]=[CH:27][C:22]([CH2:23][N:24]=[C:25]=[O:26])=[CH:21][CH:20]=1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:25]([NH:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:30])[F:29])=[CH:28][CH:27]=1)=[O:26])[CH:8]=[C:7]([C:13]([F:14])([F:16])[F:15])[CH:6]=2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(N)cc(C(F)(F)F)cc2cn1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)cc2cn1

Procedure:
Prepared from 3-methyl-7-(trifluoromethyl)isoquinolin-5-amine (Description 74) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 428 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][N:28]=1>>[NH2:26][C:27]1[N:28]=[CH:29][C:30]([NH:33][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:4]=3)=[O:10])=[CH:19][CH:18]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc(N)nc1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Product: Nc1ccc(NC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)cn1

Procedure:
50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,5-diaminopyridine via Procedure G. The prodcut was purified on reverse phase HPLC to yield N1-(6-aminopyridin-3-yl)-N4-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 444 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>ClC1C=CC=CC=1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:6]2[CH:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Nc1cc(Cl)nc(N)n1
Solvent: Clc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)nc(N)n2)CC1
Yield: 90.4 %

Procedure:
A mixture of 2,6-diamino-4-chloropyrimidine (2.88 g, 20 mmol) and 1- (tert-butoxycarbonyl)piperazine (5.6 g, 30 mmol) in chlorobenzene (30 ml) was stirred under reflux for 3 hours. After cooling the formed precipitate was collected and stirred with aqueous 1N NaOH (63 ml) at room temperature for 15 minutes. The solids were collected, washed with water and dried, yield: 90.4%, mp. 176°-179° C.
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[N:20]#[C:21][NH2:22].O>CCCCCC.C(OCC)(=O)C>[NH2:22][C:21]1[N:1]=[C:2]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:20]=1
Reactant: N#CN
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N)nc1C(C)C
Reaction time: 5 h
Yield: 22 %

Procedure:
5.00 g of methyl 2-[1-amino-1-(4-fluorophenyl)-methylene]-4-methyl-3-oxopentanoate (18.7 mmol) were treated with 5 ml of N-N-dimethylacetamide and 15.71 g of a 50% strength aqueous cyanamide solution (187 mmol) and heated to reflux. After 5 h, the solution was poured onto 50 ml of water. The mixture was cooled in an ice bath and the deposited precipitate was isolated by means of a suction filter. After drying, 2.72 g of crude product were obtained in the form of a yellowish solid. After flash chromatography (150 g of silica gel; eluent: hexane/ethyl acetate 3:2), 1.19 g of methyl 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidine-5-carboxylate were isolated in the form of a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([CH3:18])=[CH:5]2.CN([CH:22]=[O:23])C.C([Li])(C)(C)C.CCCCCCC>C1COCC1.CCOC(C)=O.CC(O)=O>[CH:22]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]([CH3:18])=[CH:5]2)=[O:23]
Reactant: Cc1cc2cc(Br)ccc2n1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc2cc(C=O)ccc2n1C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 6 %

Procedure:
A solution of 5-bromo-2-methyl-1-t-butyloxycarbonylindole (1.55 g, 5.0 mmol) and DMF (0.39 mL, 5.0 mmol) in anhydrous THF (15 mL) was cooled with stirring to −78° C. A solution of t-butyl lithium in heptane (1.7M, 7.35 mL, 12.5 mmol) was added dropwise over 5 min. The reaction mixture was then stirred for 1 h. HOAc (1 mL) was added and the reaction mixture was diluted with EtOAc (50 mL). The organic mix was washed three times with a 10% KHSO4 solution (10 mL), once with a saturated NaHCO3 solution and once with brine. The organic solution was dried over MgSO4, filtered and concentrated in vacuo. Column chromatography (EtOAc:hexane::95:5) afforded three products after removal of solvent in vacuo: (1) 1,5-di-(t-butyloxycarbonyl)-2-methylindole, an oil (89 mg, 6% yield, Rf=0.8): 1H NMR (CDCl3, 300 MHz): 8.10 (d, 1H, J=8), 8.09 (s, 1H), 7.87 (d, 1H, J=8), 6.37 (s, 1H), 2.60 (s, 3H), 1.69 (s, 9H), 1.62 (s, 9H); (2) the title product, a light orange solid (726 mg, 56% yield, Rf=0.5): 1H NMR (CDCl3, 300 MHz): 10.0 (s, 1H0, 8.24 (d, 1H, J=8), 7.97 (d, 1H, J=2), 7.77 (dd, 1H, J=8, 2), 6.44 (s, 1H), 2.62 (d, 3H, J=1), 1.70 (s, 9H); (3) 5-formyl-2-methylindole, a light orange solid (139 mg, 17% yield, Rf=0.3): 1H NMR (CDCl3, 300 MHz): 10.0 (s, 1H), 8.20 (br s, 1H), 7.71 (d, 1H, J=1), 7.68 (d, 1H, J=8), 7.37 (d, 1H, J=8), 6.37 (t, 1H, J=1), 2.48 (d, 3H, J=1); MS (ES+): 160 (C10H10NO, M++H).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:28][C:29]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:30]=1[CH:31]=O>O1CCCC1>[CH:31]([C:30]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:29]=1[F:28])=[CH2:2]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1cc(OC)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
39.4 g of methyltriphenylphosphonium iodide and 10.9 g of potassium t-butoxide were suspended in 150 ml of tetrahydrofuran. The resulting suspension was stirred at 0° C. under nitrogen stream for 30 minutes, followed by the dropwise addition thereto of a solution of 10 g of 2-fluoro-5-methoxybenzaldehyde in 20 ml of tetrahydrofuran. The resulting mixture was further stirred for one hour, quenched by the addition of water and extracted with ethyl acetate. The formed organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was subjected to silica gel column chromatography (developer: 5% ethyl acetate/n-hexane) to give 9.1 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)#[N:2].Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[OH:13][N:12]=[C:1]([C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1)[NH2:2]
Reactant: N#Cc1c[nH]c(=O)[nH]c1=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=NO)c1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 72.5 %

Procedure:
5-Cyano uracil (2.0 g, 14.6 mmol) was suspended in methanol (50 mL), then hydroxylamine hydrochloride (1.4 g, 20.0 mmol) and triethylamine (2.8 mL, 20.0 mmol) were added and the mixture was heated to reflux overnight. The mixture was cooled to room temperature, the solid was collected by filtration, washed with methanol and dried to give the title compound as a pale yellow solid (1.8 g).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]([F:40])([F:39])[CH2:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>CCCCCCC.CCOC(C)=O>[CH3:25][N:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:35]1[C:30]([O:29][CH2:28][C:27]([F:39])([F:26])[F:40])=[N:31][CH:32]=[CH:33][CH:34]=1)[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: OB(O)c1cccnc1OCC(F)(F)F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OCC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2-(2,2,2-trifluoroethoxy)pyridin-3-ylboronic acid (Combi-Blocks Inc.) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Colorless solid (58%). MS (ESI): m/z=524.103 [M+H]+.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)CC([O-])=O.[Na+].[Na+].CO.[Na]C([Na])(C(O)=O)C(O)=O.[CH2:31](Cl)/[CH:32]=[CH:33]/[CH2:34]Cl>C(O)C.CO>[CH:32]([CH:33]1[CH2:34][C:3]1([C:2]([O:9][CH3:10])=[O:8])[C:4]([O:6][CH3:7])=[O:5])=[CH2:31]
Reactant: ClC/C=C/CCl
Reactant: COC(=O)CC(=O)OC
Agent: O=C(O)C([Na])([Na])C(=O)O
Agent: O=C([O-])CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C=CC1CC1(C(=O)OC)C(=O)OC
Temperature: 60 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
To a solution of 36.6 g (1.6 g-atom) of sodium in 500 ml of anhydrous ethanol was added 105.5 g (0.80 mol) of dimethyl malonate. After several minutes, while maintaining the temperature at 60° C., 250 ml anhydrous methanol was added to solubilize the precipated sodium malonate salt. The freshly prepared disodiomalonate methanol solution was added to 100.0 g (0.80 mol) trans 1,4-dichlorobutene-2 heated to 60°-70° C. at a rate to allow a gentle reflux in the condenser. When the addition was completed, the reaction mixture was refluxed with stirring for an additional 4 hours. The reaction mixture was then cooled to ambient temperature, filtered and the resulting filtrate concentrated. Distillation of the crude product under reduced pressure afforded 82 g (44.5%) of the desired product dimethyl 2-vinylcyclopropane-1,1-dicarboxylate. B.p. 73°-78° at 1.25 mm Hg; nD24 1.4612; [lit. B.p. 71°- 73° (1 mm); nD25 1.4602].
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.[B:42](OC(C)C)([O:47]C(C)C)[O:43]C(C)C>C1COCC1>[C:30]([O:29][C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH2:20][C:17]2[CH:16]=[C:15]([B:42]([OH:47])[OH:43])[C:14]([F:13])=[N:19][CH:18]=2)[CH2:26][CH2:25]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(F)nc2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 36.1 mL, 90 mmol) was added to a stirred solution of diisopropylamine (12.8 mL, 90 mmol) in tetrahydrofuran (150 mL, 75 mmol) at −40° C. and the slightly yellow solution was stirred at the same temperature for 1 h, and then cooled to −78° C. A solution of tert-butyl 4-((6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (22.22 g, 75 mmol) in THF (100 mL) was cannulated slowly into the LDA solution over 30 min. The brown mixture was stirred at the same temperature for 1.5 h and then a solution of triisopropyl borate (25.9 mL, 113 mmol) in THF (50 mL) was added slowly. The resulting mixture was stirred at the same temperature for 30 min and then the cooling bath was removed. After the reaction mixture had warmed up to room temperature, the yellow heterogeneous mixture was quenched with 1.0 M NaOH(aq) (50 mL) and stirred for an additional 30 min. The separated aqueous layer was carefully acidified with 5N aqueous HCl until acidic (pH 4 to about 5) and the resulting cloudy mixture was diluted with EtOAc (150 mL). The separated aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic phases were dried (Na2SO4), filtered, and concentrated to give 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (21.93 g, 64.7 mmol, 86% yield) as a pale yellow solid. LCMS (API-ES) m/z 340 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[C:4]([Cl:18])[CH:3]=1.[C:19]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Cl:18][C:4]1[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:26][CH:27]=2)[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][NH:9]2
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: Nc1cc(Cl)c2c(c1)N(C(=O)C(F)(F)F)CCC2
Product: O=C(Nc1cc(Cl)c2c(c1)NCCC2)c1ccc(-c2ccccc2)nc1

Procedure:
Using the procedure outlined in Example 38, the title compound was prepared from 7-amino-5-chloro-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D104) (50 mg, 0.251 mmol) and 6-phenyl nicotinic acid (60 mg, 0.302 mmol) as a white solid (55 mg). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.11 (s, 1H), 8.22 (dd, 1H), 8.05 (dd, 1H), 7.85 (d, 1H), 7.65 (br-s, 1H), 7.45-7.55 (m, 3H), 7.00 (br.s, 1H), 6.79 (d, 1H), 4.10 (br-s, 1H), 3.25-3.30 (m, 2H), 2.75-2.80 (m, 2H), 1.95-2.00 (m, 1H), 1.57 (s, 6H). MS(ES): MH+ 364.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4](S(C)=O)[N:3]=1.[CH3:22][NH2:23]>C(O)C>[NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([NH:23][CH3:22])[N:3]=1
Reactant: CS(=O)c1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Reactant: CN
Solvent: CCO
Product: CNc1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Temperature: 180 °C

Procedure:
A suspension of 1.6 grams (0.005 mole) of 4-amino-2-methylsulfinyl-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (prepared as in Example 17) and 10 mL of aqueous 40% methylamine in 50 mL of ethanol is placed in a glass tube, which is then sealed. The sealed tube is heated at about 180° C. for 7 hours and then is cooled in an ice-bath and opened. The reaction mixture is concentrated under reduced pressure to a residue. The residue is stirred with an aqueous 10% potassium carbonate solution, and the resultant suspension is extracted with chloroform. The extract is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, yielding 4-amino-2-methylamino-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]([NH2:22])[CH3:21])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:23](N1C=CN=C1)([N:25]1C=CN=C1)=[O:24]>C(O)=O>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH:20]([NH:22][C:23]([NH2:25])=[O:24])[CH3:21])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(N)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O=CO
Product: CC(CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1)NC(N)=O

Procedure:
3-[4-(6-Isopropoxypyridin-3-yloxy)phenyl]-1-methylpropylamine (115 mg, 0.38 mmol) was reacted with formic acid and 1,1′-carbonyldiimidazole in analogy to example 44. Yield: 5 mg (4%), M+H+: 344.19.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:34]([O:36][CH3:37])=[O:35])=[N:12][C:13]([C@@H:17]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].S(OC)(O[CH3:44])(=O)=O.C(O)(=O)C>O1CCOCC1.C(OCC)(=O)C.O>[CH3:37][O:36][C:34]([C:11]1[N:12]=[C:13]([C@@H:17]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[N:14]([CH3:44])[C:15](=[O:16])[C:10]=1[O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:35]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1nc([C@@H]2CC(F)(F)CN2C(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1nc([C@@H]2CC(F)(F)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 38 °C
Reaction time: 0.75 h

Procedure:
Methyl 5-(benzoyloxy)-2-{(2S)-1-[(benzyloxy)carbonyl]-4,4-difluoropyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate dissolved in dry 1,4-dioxane was added to a suspension of LiH (1.4 eq.) in dioxane. The mixture was stirred at 38° C. for 45 minutes and then cooled down to room temperature. Dimethyl sulphate (1.3 eq.) was added and the mixture was warmed to 58° C. for 1 hour. The reaction mixture was cooled down to 16° C. and glacial acetic acid (0.1 eq) was added, followed by water and ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated to an oil which was cromatographed through silica gel (eluent: ethyl acetate:petroleum ether=3:7) to give the desired compound as a 1:1 mixture of two rotamers by 1H NMR