Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:13](C=O)C>C1(C)C=CC=CC=1.S(Cl)(Cl)=O>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(N)=O)c(Br)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of 2-bromo-4-methylbenzoic acid (15.0 g, 69.8 mmol) in toluene (60 mL), thionyl chloride (10.3 mL) and DMF (0.10 mL) were added and stirred at 50° C. for 3 h. After cooling to room temperature, the excess thionyl chloride was removed in vacuo. The residue was dissolved in toluene (50 mL), and the mixture was added to the solution of ammonia (25%, 60 mL). The white precipitate was filtered over Celite and dried in vacuo to afford 2-bromo-4-methylbenzamide (14.8 g, 99%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[NH:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:40][CH2:39][CH:36]1[CH2:37][CH2:38][N:33]([C:15](=[O:17])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:28][C:29]([F:31])([F:32])[F:30])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:34][CH2:35]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: OCC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC(CO)CC3)ccc21
Yield: 80.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]amide (73 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (75 mg), 4-piperidinemethanol (20 mg), HBTU (73 mg), and DIEA (42 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 563.8. 1H NMR (DMSO-d6, 400 MHz): δ 8.48 (t, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.79 (d, 1H), 7.67 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.37 (d, 1H), 4.14 (d, 2H), 3.92 (d, 1H), 3.67 (s, 3H), 3.27 (d, 2H), 3.02 (t, 1H), 2.58 (t, 1H), 1.78-1.55 (m, 3H), 1.20-0.90 (m, 2H), —OH and —NH proton signal was not observed.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]([NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])[C:12](=O)[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][C:11]1[N:15]=[C:16]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[F:24])[O:25][C:12]=1[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(CCOCc1ccccc1)NC(=O)c1ccc(Br)cc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(Br)cc2F)nc1CCOCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirring solution of N-[1-(2-benzyloxy-ethyl)-2-oxo-propyl]-4-bromo-2-fluoro-benzamide (1.0 mmol) (See Intermediate 36) in dimethylformamide (0.25M), slowly add phosphorus oxychloride (3.0 mmol) and heat to 90° C. for 2.5 hours. After this time, remove the heat and carefully add water (same amount as DMF) and allow the reaction to cool to room temperature before extracting with ether. Wash organics with water and brine. Dry the organics with sodium sulfate, filter and concentrate in vacuo. Purify via radial chromatography eluting with ethyl acetate and hexane. MS (m/e) (79Br/81Br): 390.2/392.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH2:14])[CH:7]=1.[N:17]1[N:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]2=[C:19]([C:26](O)=[O:27])[CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[NH:14][C:26]([C:19]2[CH:18]=[N:17][N:21]3[CH:22]=[CH:23][CH:24]=[N:25][C:20]=23)=[O:27])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1c(N)cnn1C
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-amine (0.100 g, 0.421 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (77.2 mg, 0.473 mmol, 1.12 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (269 mg, 0.519 mmol, 1.23 eq), N,N-diisopropylethylamine (0.15 mL, 0.86 mmol, 2.0 eq), and 4-dimethylaminopyridine (20.1 mg, 0.164 mmol, 0.39 eq) in 5.0 mL N,N-dimethylformamide was stirred at 50° C. for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 82.2 mg (51%) of N-(5-(5-chloro-2-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=383.0; 1H NMR (400 MHz, DMSO-d6) δ: 9.51 (s, 1H), 9.31 (d, 1H), 8.67 (d, 1H), 8.63 (s, 1H), 7.98 (s, 1H), 7.58 (d, 1H), 7.54 (s, 1H), 7.31 (d, 1H), 7.28 (d of d, 1H), 3.85 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: N1CC[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[CH:22][N:23]([CH3:25])[CH3:24])[C:14]2=[O:26])[CH:10]=[CH:11][CH:12]=1>C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[CH:22][N:23]3[CH2:24][CH2:3][CH2:2][CH2:25]3)[C:14]2=[O:26])[CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)C=C1C(=O)N(c2cccc(Cl)c2)c2ccccc21
Reactant: C1CCNC1
Solvent: CCO
Product: O=C1C(=CN2CCCC2)c2ccccc2N1c1cccc(Cl)c1
Reaction time: 3 h

Procedure:
Pyrrolidine (0.42 ml, 5.0 mmoles) was added to a solution of the title product of Example A3 (0.3 g, 1.0 mmole) in 10 ml of ethanol. The mixture was stirred 3 hours and then allowed to stand for 16 hours at 25°. The reaction mixture was evaporated to dryness in vacuo. The residue was triturated with ether and filtered with pentane wash to yield purified title product, 0.253 g; m.p. 108°-112°.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([O:17][CH3:18])[C:6](=[O:16])[CH:7]=[C:8]1[C:12](=O)[O:11]C(C)(C)[O:9]1.[CH3:24][S:25]([NH2:28])(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([O:17][CH3:18])[C:6](=[O:16])[CH:7]=[C:8]([OH:9])[C:12]([NH:28][S:25]([CH3:24])(=[O:27])=[O:26])=[O:11]
Reactant: CS(N)(=O)=O
Reactant: CON(Cc1ccc(F)cc1Cl)C(=O)C=C1OC(C)(C)OC1=O
Product: CON(Cc1ccc(F)cc1Cl)C(=O)C=C(O)C(=O)NS(C)(=O)=O
Yield: 45.8 %

Procedure:
Reaction of N-(2-chloro-4-fluoro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methoxy-acetamide (0.175 g, 0.51 mmol) with methanesulfonamide (0.073 g, 0.77 mmol) as described in the preparation of compound 22 gave 0.089 g (45% yield) of the title amide as a white solid after crystallization from ethyl acetate-hexane; mp=144° C. (decomposition). 1H NMR (400 MHz, CDCl3) δ: 3.36 (3H, s, SO2CH3), 3.71 (3H, s, OCH3), 4.96 (2H, s, NCH2), 6.60 (1H, s, CH), 6.95-7.32 (3H, m, aromatics), 8.96 (1H, broad s, NH). Anal. calcd for C13H14ClFN2O6S: C, 41.00; H, 3.70; N, 7.35; found: C, 41.03; H, 3.61; N, 7.29.
Reaction SMILES: [CH2:1]([N:8]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[NH:9]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH2:1]([N:8]([C:17]([NH:19][CH2:20][CH3:21])=[O:18])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)N(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)N(N)Cc1ccccc1
Yield: 91.6 %

Procedure:
A solution of of 2-benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide (2.8 g, 9.6 mmol) in 50% trifluoroacetic acid in dichloromethane (10 ml) was stirred for 10 min at room temperature. Then saturated sodium bicarbonate was added until pH>7 and the aqueous layer was extracted with dichloromethane (2×10 ml) and the combined organic layers were dried (magnesium sulfate) and concentrated in vacuo. The obtained oil was chromatographed on silica (100 g) with ethyl acetate as eluent to give 1.7 g of 2-benzyl-4-ethylsemicarbazide.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([CH:7]=[CH:8][C:9]3[O:10][C:11](=[O:18])[C:12]([CH3:17])([CH3:16])[C:13]=32)=[CH:5][C:4]=1[C:19]#[N:20].[NH:21]1[CH:25]=[N:24][CH:23]=[N:22]1.[Na].O>CN(C)C=O>[CH3:16][C:12]1([CH3:17])[C:11](=[O:18])[O:10][C:9]2[CH:8]=[CH:7][C:6]3[C:14]([C:13]1=2)=[CH:15][C:3]([CH2:2][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)=[C:4]([C:19]#[N:20])[CH:5]=3
Reactant: c1nc[nH]n1
Reactant: CC1(C)C(=O)Oc2ccc3cc(C#N)c(CBr)cc3c21
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)Oc2ccc3cc(C#N)c(Cn4cncn4)cc3c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 8-bromomethyl-1,2-dihydro-1,1-dimethyl-2-oxonaphtho[2,1-b]furan-7-carbonitrile in N,N-dimethylformamide (3 ml) was treated with sodium 1,2,4-triazole (0.18 g) and the mixture was stirred at room temperature for 4 h, then treated with water (20 ml). The mixture was extracted twice with ethyl acetate and the combined extracts were dried and evaporated to dryness under reduced pressure. The residue was purified by flash chromatography using methanol:ethyl acetate, 1:99 v/v, as eluant to give 1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho(2,1-b)-furan-7-carbonitrile, m.p. 198°-198° after recrystallisation from a mixture of ethyl acetate and cyclohexane.
Reaction SMILES: C1(C[O:5][C:6](=[O:31])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:14]([Cl:30])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[Cl:30][C:14]1[CH:13]=[C:12]([CH:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([OH:31])=[O:5])[CH:17]=[C:16]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:15]=1[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc(Cl)cc2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc(Cl)cc2)c(OCC2CC2)c1
Yield: 102.3 %

Procedure:
2-(2,4′-Dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.18 g, 0.36 mmol) was dissolved in a mixture of EtOH and H2O (9 mL/1 mL) and KOH (0.2 g, 3.6 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5 and the reaction mixture was extracted with EtOAc (3×10 mL). The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 2-(2,4′-dichloro-6-cyclopropylmethoxy-biphenyl-4-yl)-4-methyl-pentanoic acid as a yellowish solid (0.15 g, 93%). M.p.=52-53° C. 1H NMR (300 MHz, CDCl3/TMS): δ 10.60 (br s, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 6.83 (s, 1H), 3.75 (d, J=6.3 Hz, 2H), 3.63 (t, J=7.3 Hz, 1H), 1.99-1.93 (m, 1H), 1.74-1.65 (m, 1H), 1.59-1.51 (m, 1H), 1.11-1.00 (m, 1H), 0.94 (d, J=6.3 Hz, 6H), 0.54-0.40 (m, 2H), 0.22-0.12 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.7, 157.2, 139.7, 134.0, 133.4, 133.1, 131.8, 128.5, 127.9, 121.6, 111.3, 73.3, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][N:14]([CH3:23])[C:15]1[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][N:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][N:14]([CH3:23])[C:15]1[C:20]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CN(C)c1ncccc1C=O
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CN(C)c1ncccc1C=C1N=C(c2cccs2)OC1=O
Temperature: 90 °C
Yield: 32.3 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 2-(dimethylamino)-3-pyridinecarboxaldehyde (50 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 29 mg of the above-captioned compound.
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:10](Br)[C:11]#[CH:12]>>[CH2:8]([O:7][C:5]([C:1]1([CH2:12][C:11]#[CH:10])[CH2:4][CH2:3][CH2:2]1)=[O:6])[CH3:9]
Reactant: C#CCBr
Reactant: CCOC(=O)C1CCC1
Product: C#CCC1(C(=O)OCC)CCC1

Procedure:
In analogy to the procedure described in example 24C], reaction of ethyl cyclobutanecarboxylate and propargyl bromide gave the title compound as brown liquid.
Reaction SMILES: [CH:1]([NH:4][C:5]([CH:7]1[CH2:12][N:11]([C:13](OC(C)(C)C)=O)[CH2:10][CH2:9][N:8]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.ClC1[N:43]=[CH:42][N:41]=[C:40]([NH:44][C:45]2[S:46][C:47]([C:50]#[N:51])=[CH:48][N:49]=2)[CH:39]=1.C(N(CC)CC)C>>[C:50]([C:47]1[S:46][C:45]([NH:44][C:40]2[N:41]=[CH:42][N:43]=[C:13]([N:11]3[CH2:10][CH2:9][N:8]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[CH:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12]3)[CH:39]=2)=[N:49][CH:48]=1)#[N:51]
Reactant: CC(C)NC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)C1CN(c2cc(Nc3ncc(C#N)s3)ncn2)CCN1C(=O)OCc1ccccc1
Temperature: 150 °C

Procedure:
47-2 (0.24 g, 0.78 mmol) was first treated with 3 mL of trifluoroacetic acid for 30 minutes at 25° C. and then the reaction was evaporated to dryness. The residue was dissolved in n-butanol and 35-1 (0.18 g, 0.78 mmol) and triethylamine (0.39 g, 3.88 mmol) were added. After heating at 150° C. for 18 hours, the reaction was cooled and the product was filtered off, washed with n-butanol, ethyl ether and then dried to afford the product 47-3. Hi-Res MS: calc: 507.1921 found: 507.1914. 1H-NMR (DMSO-d6): 12.15(s, 1H); 8.39(s, 1H); 8.25(s, 1H); 7.33(m, 5H); 6.11(s, 1H); 5.14(m, 2H); 4.47(m, 2H); 3.85(m, 2H); 3.69(m, 2H); 3.25(m, 1H); 3.17(m, 1H); 0.93(m, 6H).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][NH:6][CH3:7])[CH3:2].Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][N:6]([CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])[CH3:7])[CH3:2]
Reactant: CCN(CC)CCNC
Reactant: O=C(O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCN(C)Cc1cccc(C(=O)O)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
Into a 1000-mL round bottom flask, was placed a solution of N1,N1-diethyl-N2-methylethane-1,2-diamine (9.1 g, 63.00 mmol, 1.50 equiv, 90%) in N,N-dimethylformamide (500 mL), 3-(bromomethyl)benzoic acid (10 g, 46.51 mmol, 1.00 equiv), potassium carbonate (7.8 g, 56.12 mmol, 1.20 equiv), and potassium iodide (1.55 g, 9.34 mmol, 0.20 equiv). The resulting solution was stirred for 2 h at 90° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (10 g) was purified by reverse phase HPLC eluting with 0.05% TFA in a water/CH3CN gradient. The product was obtained as 6 g (46%) of a white solid. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.01 (m, 1H), 7.89-7.87 (m, 1H), 7.28-7.22 (m, 2H), 3.99 (s, 2H), 2.97-2.72 (m, 8H), 2.28 (s, 3H), 1.13-1.01 (m, 6H). MS (ES, m/z): 265 [M+H]+.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)(=O)=O.[C:22]([NH2:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCC>C(OCC)(=O)C>[C:5]1([NH:30][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: NC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc3ccccc23)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2ccccc12)c1ccccc1
Yield: 94.6 %

Procedure:
Following the general procedure, 1-naphthyl tosylate (149 mg, 0.5 mmol) was coupled with benzamide (90 mg, 0.75 mmol) with the reaction time of 20 h. Chromatography on silica gel column with 4:1 hexane:ethyl acetate gave 117 mg (95%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[NH:24][C:25]1[CH:26]=[C:27]([NH:32][C:33]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:36]=2)=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Product: COc1cc2c(Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)ncnc2cc1OCCCN1CCOCC1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline was reacted with N-(3-amino-4-methylphenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 58% yield; NMR: 1.96 (m, 2H), 2.13 (s, 3H), 3.29 (m, 4H), 3.5 (m, 4H), 3.59 (m, 4H), 3.69 (m, 4H), 3.92 (s, 3H), 4.18 (m, 2H), 7.08 (m, 1H), 7.13 (s, 1H), 7.22 (s, 1H), 7.28 (m, 1H), 7.58 (m, 1H), 7.75 (m, 1H), 7.81 (s, 1H), 8.27 (m, 2H), 9.39 (s, 1H), 10.29 (s, 1H); m/s: M+H+ 614.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[N:23]([C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1)=[C:24]=[O:25].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH:15][C:24](=[O:25])[NH:23][C:26]2[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NC(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (Intermediate 39) (112 mg, 0.329 mmol) and DCM (3 mL) was added ethyl 4-isocyanatobenzoate (65 mg, 0.340 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.172 mL, 0.986 mmol). The solution was stirred at rt. After 20 minutes, the reaction product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep®pre-packed silica gel column (4 g), eluting with 70% to 90% EtOAc in hexane, to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][C@@:2]12[CH2:19][CH2:18][C@@H:17]3[C@:12]([CH3:22])([CH2:13][CH2:14][CH2:15][C:16]3([CH3:21])[CH3:20])[C@H:11]1[CH2:10][S:9][C:8]1[C:3]2=[C:4]([OH:24])[CH:5]=[C:6]([OH:23])[CH:7]=1.[CH3:25][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:25][O:23][C:6]1[CH:7]=[C:8]2[C:3]([C@@:2]3([CH3:1])[C@H:11]([CH2:10][S:9]2)[C@:12]2([CH3:22])[C@H:17]([C:16]([CH3:20])([CH3:21])[CH2:15][CH2:14][CH2:13]2)[CH2:18][CH2:19]3)=[C:4]([OH:24])[CH:5]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC1(C)CCC[C@]2(C)[C@H]3CSc4cc(O)cc(O)c4[C@]3(C)CC[C@@H]12
Solvent: CO
Solvent: ClCCl
Product: COc1cc(O)c2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C

Procedure:
(1R,10R,11S,16S)-1,11,15,15-Tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-3,5-diol (Compound No. 26) (346 mg, 1.0 mmol) was dissolved in MeOH (4 mL) and CH2Cl2 (12 mL). Trimethylsilyl diazomethane (0.80 mL, 2.0 M in ether, 1.6 mmol) was added portionwise over 29 h at room temperature, monitoring the reaction by 1H NMR. The mixture was then concentrated and purified by chromatography on silica gel (Hexanes/EtOAc, 4:1) followed by recrystallization from MeOH/water to give (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-ol (Compound No. 29) (142 mg, 39%) as a white solid. 1H NMR (CDCl3): δ 6.21 (d, 1H), 5.95 (d, 1H), 4.72 (s, 1H), 3.69 (s, 3H), 3.30 (m, 1H), 2.91 (m, 1H), 2.78 (m, 1H), 1.85-1.40 (m, 8H), 1.39 (s, 3H), 1.20-1.00 (m, 2H), 0.96 (s, 3H), 0.95 (m, 1H), 0.85 (s, 3H), 0.84 (s, 3H). MS m/z 359 (C22H32O2S−H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[N:10]=[C:9]2[CH:20]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:22]1([CH2:27][C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:26][CH2:25][CH2:24][CH2:23]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:20][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[C:28]([CH2:27][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH:29]=1)[N:8]([C:7]1[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:17]2=[O:18]
Reactant: Cc1ncccc1-n1c(C=O)nc2ccc(F)cc2c1=O
Reactant: Nc1cccc(CN2CCCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1ncccc1-n1c(CNc2cccc(CN3CCCC3)c2)nc2ccc(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(2-methyl-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.158 g, 0.56 mmol), 3-pyrrolidin-1-ylmethylaniline (0.050 g, 0.28 mmol), and acetic acid (0.16 mL, 2.8 mmol) in dichloroethane (15 mL) was chilled to 0° C. and sodium triacetoxyborohydride (0.297 g, 1.4 mmol) was added. The reaction was stirred for 1 hour at 0° C. and then allowed to warm to ambient temperature and stirred for 16 hours. The reaction was quenched by addition of saturated aqueous bicarbonate and continued stirring for 30 minutes. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (35 g) with elution proceeding as follows: 10% methanol/0.5% ammonium hydroxide/chloroform (50 mL), nil; (75 mL), unweighed impurity; (50 mL), unweighed 3-(2-methyl-pyridin-3-yl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; (50 mL), unweighed mixed fraction; (100 mL), 0.031 g (25%) of 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-[(3-pyrrolidin-1-ylmethyl-phenylamino)-methyl]-3H-quinazolin-4-one as a yellow foam which had: 1H NMR δ 8.72 (d, J=5 Hz, 1H), 7.92 (dd, J=3, 8 Hz, 1H), 7.82 (dd, J=5, 9 Hz, 1H), 7.58-7.52 (m, 2H), 7.39 (dd, J=5, 8 Hz, 1H), 7.08 (t, J=8 Hz, 1H), 6.67-6.64 (m, 2H), 6.37 (d, J=8 Hz, 1H), 5.10 (s, 1H), 3.90 (dd, J=4.5, 17 Hz, 1H), 3.70 (dd, J=5, 17 Hz, 1H), 3.56 (ABq, Δv1-3=21 Hz, J=12.5 Hz, 2H), 2.54 (s, 4H), 2.36 (s, 3H), 1.78 (s, 4H); APCI MS m/z=444 (P+1).