Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]2[CH2:8][CH2:9][C:10](=[O:11])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(Cl)cc2)=NN1
Yield: 81.5 %

Procedure:
To a solution of 3-(4-chlorobenzoyl)propionic acid (20 g) in absolute ethanol (200 ml) was added 5 g of hydrazine monohydrate. A thick solid was formed which dissolved after heating. The resulting solution was refluxed for 3 h, cooled and the solid formed filtered and dried to yield 16 g (80%) of 6-(4-chlorophenyl)-4,5-dihydropyridazinone.
Reaction SMILES: O=C1[NH:6][CH:5]([CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[C:4](=[O:24])N1.[OH2:25].[OH-].[Ba+2].[OH-]>O>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][C@@H:5]([C:4]([OH:24])=[O:25])[NH2:6])[CH:9]=3)[NH:13][CH:12]=2)[CH2:18][CH2:19]1
Reactant: O
Reactant: CN1CCC(c2c[nH]c3ccc(CC4NC(=O)NC4=O)cc23)CC1
Agent: [Ba+2]
Agent: [OH-]
Product: CN1CCC(c2c[nH]c3ccc(C[C@H](N)C(=O)O)cc23)CC1
Yield: 58.7 %

Procedure:
A solution of the product from step (d) (2.4 g) and barium hydroxide hydrate (8.4 g) in water (50 ml) was refluxed for 72 hours, then cooled and evaporated in vacuo. The residue was taken up in hot methanol and filtered to remove barium salts. The filtrate was evaporated in vacuo, the residue dissolved in water and dry ice added to precipitate barium carbonate. The latter was filtered off and the filtrate evaporated in vacuo to give the desired product as a yellow foam (1.3 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[OH:36].[F-].[Cs+]>COCCOC.CO.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>[OH:36][C:22]1[CH:23]=[CH:24][C:25]([C:2]2[CH:10]=[C:9]3[C:5](/[C:6](=[CH:12]/[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)/[C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)=[CH:26][C:21]=1[O:20][CH3:19]
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1ccccn1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COc1cc(-c2ccc3c(c2)NC(=O)/C3=C\c2ccccn2)ccc1O
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of Example 2A (80 mg, 0.26 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.31 mmol), Pd(PPh3)4 (30 mg, 0.026 mmol), and CsF (43 mg, 0.29 mmol) in DME/methanol (2:1) was stirred at 80° C. for 18 hours, cooled to room temperature, concentrated, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by HPLC (Zorbax C-18 column) with 10-100% acetonitrile/water to provide the desired product (17 mg, 18%). MS (DCI/NH3) m/z 345.1 (M+H)+; 1H NMR (300 MHz, CD3OD) δ8.92 (d, 1H, J=5.5 Hz), 8.82 (d, 1H, J=7.8 Hz), 8.25 (s, 1H), 7.89 (m, 1H), 7.71 (s, 1H), 7.62 (m, 1H), 7.41 (m, 1H), 7.24 (d, 1H, J=1.7 Hz), 7.14 (dd, 1H, J=8.1, 2.0 Hz), 7.08 (dd, 1H, J=5.8, 2.1 Hz), 6.99 (d, 1H, J=8.1 Hz), 3.98 (s, 3H); Anal. Calcd. for C21H16N2O3.1.5CF3CO2H: C, 73.24; H, 4.68; N, 8.13. Found: C, 56.40; H, 3.57; N, 5.005.
Reaction SMILES: [Na].[CH3:2][C:3]([SH:6])([CH3:5])[CH3:4].Br[CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Cl-].[Na+]>C(O)C.O>[CH3:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][S:6][C:3]([CH3:5])([CH3:4])[CH3:2]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(C)(C)S
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(C)(C)SCC(=O)C(C)(C)C
Temperature: 0 °C

Procedure:
To a solution of 5.8 g (0.25 mol) of sodium metal in 175 ml of absolute ethanol is added, dropwise, 24.4 g (0.27 mol) of 2-methyl-2-propanethiol. The stirred solution is heated for 20 minutes, cooled, and treated in a dropwise manner with 44.8 g (0.25 mol) of 1-bromopinacolone, prepared according to the procedure of J. Am. Chem. Soc., 74, 4507 (1952). This reaction mixture is heated at reflux for 20 minutes, cooled, and poured onto 200 g of ice and water. After being saturated with sodium chloride, the mixture is extracted with four portions of ether. The combined ether extracts are dried over anhydrous magnesium sulfate, filtered, and stripped of solvent. Distillation of the residue through a short Vigreaux column gives the desired product. Properties of this, and similar compounds prepared by substantially the same procedure using the appropriate mercaptans and -haloketones, are given in Table 1.
Reaction SMILES: C(=[O:8])C1C=CC=CC=1.[C:9]([C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][CH:37]=1)[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:26]1[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[CH:28]=[N:27]1)[NH:20][C:19]2=[O:34])#[N:10]>>[C:9]([C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][CH:37]=1)[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:26]1[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[CH:28]=[N:27]1)[NH:20][C:19]2=[O:34])(=[O:8])[NH2:10]
Reactant: O=Cc1ccccc1
Reactant: N#Cc1cccc(CNc2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1
Product: NC(=O)c1cccc(CNc2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 171, substituting 3-cyanobenzaldehyde for benzaldehyde in step A. Step C yielded a mixture of 1-[6-(3-cyano-benzylamino)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, the titled compound, and 1-[6-amino-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, which was separated by reverse-phase HPLC.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].Cl>N1C=CC=CC=1>[CH:1]1([O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccccc1OC1CCCCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1OC1CCCCC1
Temperature: 0 °C
Yield: 89.4 %

Procedure:
To 20 ml of a pyridine solution containing 2.7 g of 2-cyclohexyloxyaniline was added dropwise 1.8 g of methanesulfonyl chloride under ice cooling with stirring. After completion of the addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and made acidic with dilute hydrochloric acid. The crystals which formed were collected by filtration, washed with water and dried to give 3.8 g of the crude crystals, which were then recrystallized from ethanol-n hexane to give 3.4 g of N-(2-cyclohexyloxyphenyl)methanesulfonamide.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:12]2[CH:13]=[C:14]([C:18]([N:20]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:34])[CH2:5]1)[CH:2]=[CH2:3].[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>C(O)C>[CH2:40]([O:39][C:35](=[O:38])[CH2:36][CH2:37][N:23]1[CH2:24][CH2:25][CH2:26][N:20]([C:18](=[O:19])[C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C@@H:11]([N:7]3[CH2:8][C@@H:9]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][C@@H:6]3[CH3:34])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[CH:13]=2)[CH2:21][CH2:22]1)[CH3:41]
Reactant: C=CC(=O)OCC
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCCNCC3)c2)C[C@H]1C
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCCN(CCC(=O)OCC)CC3)c2)C[C@H]1C
Temperature: 25 °C
Yield: 62.5 %

Procedure:
The compound of Example 2 (362 mg) and ethyl acrylate (81 mg) in ethanol (10 mL) was refluxed for 4 h. TLC of reaction solution indicated a new spot and starting material. Additional ethyl acrylate (65 mg) was added to the reaction solution. The reaction was refluxed for another 6 h. After being cooled to room temperature, the reaction solution was dried by rotary evaporator. The remaining residual was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 10% MeOH in CH2Cl2) to give 3-(4-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-propionic acid ethyl ester (275 mg; 63%). 1H NMR (300 MHz, CDCl3) δ 7.59-7.47 (m, 1H), 7.39-7.22 (m, 3H), 7.09 (m, 1H), 6.63 (m, 3H), 5.89 (m, 1H), 5.21 (m, 3H), 4.14 (q, 2H, J=7.0 Hz), 3.76-3.63 (m, 2H), 3.44-3.34 (m, 3H), 2.95-2.76 (m, 5H), 2.72-2.39 (m, 8H), 2.17 (dd, 1H, J=10.0, 10.0 Hz), 2.00 (dd, 1H, J=11.0, 11.0 Hz), 1.92 (m, 1H), 1.69 (m, 1H), 1.25 (t, 3H, J=7.0 Hz), 1.15 (d, 3H, J=6.0 Hz), 1.02 (d, 3H, J=5.5 Hz); MS (FAB, glycerol) m/z: 563 (M++1), 409, 209, 153; Found C, 68.59; H, 8.30; N, 9.64. Calc. (C33H46N4O4 0.2 CH2Cl2) C, 68.78; H, 8.07; N, 9.66.
Reaction SMILES: [CH2:1]([S:3][C:4](=[O:17])[CH:5]([CH:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12]1)[C:6]([S:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:18](O)[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:9]([S:8][C:6](=[O:7])[CH:5]([CH:11]1[CH2:15][CH2:14][C:13]2([O:20][CH2:19][CH2:18][O:16]2)[CH2:12]1)[C:4]([S:3][CH2:1][CH3:2])=[O:17])[CH3:10]
Reactant: CCSC(=O)C(C(=O)SCC)C1CCC(=O)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCSC(=O)C(C(=O)SCC)C1CCC2(C1)OCCO2
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A mixture of 2-(3-oxo-cyclopentyl)-dithiomalonic acid di-S-ethyl ester (43.6 g, 0.159 mol), ethane-1,2-diol (49.3 g, 0.796 mol), p-toluenesulfonic acid (5.5 g, 0.032 mol) and benzene (500 mL) were heated to reflux and water was removed with a Dean-Stark trap. After 16 h, the mixture was quenched with water and saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried and concentrated to afford crude product. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 5% ethyl acetate/hexanes) afforded 2-(1,4-dioxa-spiro[4.4]non-7-yl)-dithiomalonic acid di-S-ethyl ester as a white solid (47.0 g, 92%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH2:18]O)([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.N1C(C)=CC(C)=CC=1C.[F:42]C(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH2:18][F:42])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CO)C3)n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C)(CF)C3)n1
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of 2-hydroxymethyl-4-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (227) (62 mg, 0.140 mmol) and 2,4,6-collidine (0.0359 mL, 0.271 mmol) in dry CH2Cl2 was added trifluoromethanesulfonic acid anhydride (0.0365 mL, 0.217 mmol) at 0° C. The mixture was stirred at 0° C. to room temperature for 1 hr. TLC indicated that the reaction was complete. The reaction was quenched with 0.5 N aqueous HCl, extracted with 3×CHCl3, dried over Na2SO4, and concentrated. The residue was dissolved in anhydrous CH2Cl2(3 mL), and TBAF (1 mL, 1 M in THF) was added. The resulting mixture was stirred at room temperature for 1.5 hr, quenched with H2O, and extracted with 3×CHCl3. The combined organic layer was dried over Na2SO4, concentrated, and purified by column chromatography eluting with 50-65% EtOAc in hexanes to give a white solid (18 mg, 28% yield). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1 H) 7.84-7.96 (m, 2 H) 7.25-7.31 (m, 2 H) 7.02-7.15 (m, 3 H) 6.72-6.83 (m, 1 H) 4.26-4.54 (m, 2 H) 3.79 (s, 3H) 3.20 (d, J=16.67 Hz, 1H) 3.08 (s, 3 H) 2.89 (dd, J=16.67, 1.77 Hz, 1 H) 1.52 (s, 3 H); LCMS for C22H22FN3O5S m/z 460.00 (M+H+).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]3[CH:18]([C:19]4[CH:23]=[CH:22][S:21][CH:20]=4)[CH2:17][NH:16][CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33](O)=[O:34])[CH:26]=[CH:25]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[C:33]([N:16]2[CH2:17][CH:18]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:14]([CH2:13][N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)[CH2:15]2)=[O:34])[CH:26]=[CH:25]1
Reactant: c1ccc(C2CCN(CC3CNCC3c3ccsc3)CC2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc2cc[nH]c12)N1CC(CN2CCC(c3ccccc3)CC2)C(c2ccsc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 0.022 g (0.067 mmol) of 3-(SR)-(4-phenyl piperidinylmethyl)-4-(RS)-(3-thienyl)pyrrolidine and 0.016 g (0.1 mmol) of indole-7-carboxylic acid in 2 mL of CH2Cl2 and 0.037 mL (0.27 mmol) of triethylamine was added 0.022 g (0.087 mL) of BOP-Cl [Bis-(2-oxo-3-oxazolidinyl)phosphinic chloride] and the reaction mixture was stirred at rt for 5 h. The reaction mixture concentrated and purified by chomatography (silica, acetone: hexanes, 1:3 to 1:2) to give the title compound. 1H NMR (CDCl3) δ; 10.02 (bs, 1H), 7.79 (bs, 1H), 7.02-7.53 (m, 11H), 6.62 (bs, 1H), 4.15-4.19 (m, 2H); Mass Spectrum (CI) m/e=482 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>C1COCC1>[C:18]1([C:15]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6])[CH2:17][CH2:16]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=C1CC(=O)O1
Reactant: NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
Diketene (1.68 mL, 21.9 mmol, 1.50 equiv) was added at 0° C. to a stirred solution of 1-(4-aminobutyl)-4,4-diphenylpiperidine (4.50 g, 14.6 mmol, 1.00 equiv) in anhydrous THF (40 mL) under argon, and stirring was continued at room temperature for 1.5 hours. The mixture was concentrated and the residual oil washed with hexane (3×50 mL) to give 5.17 g (90%) of light yellow oil, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: CN([CH:4]=[C:5]([C:9](=[O:12])[CH2:10][CH3:11])[C:6](=O)[CH3:7])C.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].C[O-].[Na+]>CO>[CH3:7][C:6]1[NH:18][C:16](=[O:17])[C:15](=[CH:4][C:5]=1[C:9](=[O:12])[CH2:10][CH3:11])[C:13]#[N:14]
Reactant: N#CCC(N)=O
Reactant: CCC(=O)C(=CN(C)C)C(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)c1cc(C#N)c(=O)[nH]c1C
Reaction time: 3 h

Procedure:
A mixture containing 34 g of 2,4-hexanedione, 50 ml of dimethylformamide and 40 ml of dimethylformamide dimethyl acetal was allowed to stand at room temperature overnight and then concentrated on a rotary evaporator at steam bath temperature to yield, as a liquid, 3-dimethylaminomethylene-2,4-hexanedione. A mixture containing said 3-dimethylaminomethylene-2,4-hexanedione, 300 ml of methanol 25.2 g of cyanoacetamide and 16.2 g of sodium methoxide was refluxed with stirring for 3 hours and then concentrated in vacuo to remove the methanol. The residue was dissolved in 300 ml of warm water and filtered. The filtrate was acidified with acetic acid and the resulting precipitate was collected, washed with water, dried in vacuo at 90°-95° C. and recrystallized from dimethylformamide (75 ml) to yield 7.8 g of 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile, m.p. 265°-268° C. with decomposition the acidic mother liquor was concentrated to dryness and digested with hot methanol and cooled. The separated solid was dried, 20.2 g, and recrystallized from dimethylformamide to yield 9.8 g of finely crystalline material, m.p. 259°-263° C. with decomposition. The NMR spectral data for this compound indicated it to be mostly said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile. The resulting mother liquors were combined and concentrated on a rotary evaporator and the resulting residue was recrystallized from ethanol to yield 20.4 g of solid, m.p. 220°-226° C. The NMR spectral data for this solid indicated it to be a 5:4 mixture of said 1,2-dihydro-6-methyl-2-oxo-5-(n-propanoyl)nicotinonitrile and 5-acetyl-6-ethyl-1,2-dihydro-2-oxonicotinonitrile. Preliminary attempts to separate the two compounds by fractional crystallizaton were unsuccessful; however, the two compounds should be separable.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH2:3]([O:4][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=1[C:12]#[N:13])[C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: CC(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 80 %

Procedure:
Prepared as in Example 215c from 2,2-dimethylpropan-1-ol and 2,6-dinitrobenzonitrile in 80% yield. MS 235 (MH+).
Reaction SMILES: CC([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])CO.C(C(CCCCCCCCCCCC)[CH2:21][OH:22])C>>[CH2:12]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH3:5])[CH2:21][OH:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCC(CC)CO
Reactant: CCCCCCCCCCCCCC(C)CO
Product: CCCCCCC(CO)CCCCCC

Procedure:
2-methyl-1-pentadecanol; 2-ethyl-1-tetradecanol;
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([S:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:7]=[CH:6][N:5]=1.[SH:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=1.[OH-].[Na+]>C(O)C>[CH3:11][O:10][C:9]1[C:4]([CH2:3][S:19][C:20]2[NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=2)=[N:5][CH:6]=[CH:7][C:8]=1[S:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1c(SCc2cccs2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(SCc2cccs2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 56 %

Procedure:
2-Chloromethyl-3-methoxy-4-(2-thienylmethylthio)pyridine hydrochloride, 2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 25° C. for 20 h. After crystallization from toluene/methanol, the title compound is isolated. Yield: 56%, m.p. 124°-127° C. 8. 2-{[[4-(2-Thienylmethylthio)-2,pyridinyl]methyl]thio}-1H-benzimidazole
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(C)C=CC=CC=1.[NH2:29][C:30]1[CH:31]=[C:32]([C:36]#[CH:37])[CH:33]=[CH:34][CH:35]=1.Cl>C(#N)C>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[CH:37])[CH:31]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: C#Cc1cccc(N)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 37.5 °C
Reaction time: 6 h
Yield: 91.9 %

Procedure:
1.98 Kg of 4-chloro-6,7-bis (2-methoxyethoxy) quinazoline was suspended in 30 litres of acetonitrile and 10 litres of toluene and 1.0 Kg of 3-aminophenyl acetylene was charged at 25-30° C. and hydrochloric acid was added. The reaction mass was heated and stirred at 35-40° C. for 6 hours. The solid obtained was filtered and washed with a mixture of acetonitrile and toluene. The product was dried at 38-40° C. to obtain 2.5 Kg of erlotinib hydrochloride.
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].N1C=CC=CC=1.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>O1CCCC1>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])=[O:22]
Reactant: CC(C)(Br)C(=O)Br
Reactant: C=CCCCCCCCCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CCCCCCCCCCOC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A similar synthetic scheme was conducted as followed.x To a solution of 4.257 g (25 mmol) of co-undecylenyl alcohol in 25 mL of dry tetrahydrofuran was added 2.1 mL of pyridine (26.5 mmol) by dropwise addition of 3.10 mL of 2-bromoisobutyryl bromide (25 mmol). The mixture was stirred at ambient temperature for 8 hours. The remaining THF was removed under reduced pressure followed by dilution with hexane (50 mL). The mixture was washed with 2 M HCl solution and twice with water (50 ml). The organic phase was dried over sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure yielding a colorless oil (89%). 1H NMR (500 MHz, CDCl3) δ: 1.22-1.45 (br m, 12H); 1.62-1.75 (m, 2H); 1.94 (s 6H); 2.05 (q, 2H, J) 6 Hz); 4.17 (t, 2H, J=9 Hz); 4.9-5.05 (m, 2H); 5.72-5.9 (m, 1H) ppm.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH:32]([NH2:35])([CH3:34])[CH3:33]>>[OH:27][C:23]1[CH:22]=[C:21]([CH:8]2[C:9]3[NH:10][C:11]4[C:16](=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4)[C:17]=3[CH2:18][C:6]3([CH3:30])[C:5](=[O:31])[N:4]([CH2:3][CH2:2][NH:35][CH:32]([CH3:34])[CH3:33])[C:28](=[O:29])[N:7]23)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)N
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNC(C)C)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and isopropyl amine as starting materials. MS: m/z (MH+)=463.2
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:17])=[C:10]([S:13](Cl)(=[O:15])=[O:14])[CH:11]=2)[C:6]([CH3:19])([CH3:18])[CH2:5]1)(=[O:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[F:17][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[S:13]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)(=[O:15])=[O:14])[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]2([CH3:19])[CH3:18]
Reactant: C1CCNC1
Reactant: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)Cl)cc21
Product: CC(=O)N1CC(C)(C)c2cc(F)c(S(=O)(=O)N3CCCC3)cc21
Yield: 64.9 %

Procedure:
The title compound was prepared starting from 1-acetyl-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole-6-sulfonyl chloride (400 mg, 1.3 mmol) and pyrrolidine (650 μL, 7.87 mmol) following similar methods to those described in Preparation 69 to give the title compound (287 mg) as a dark orange solid. MS: [M+H]+=341.