Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=2)(=[O:36])=[O:35])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[CH:17][CH:16]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, prepared in Step A of Example 11e, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.80 (d, 1H), 8.05 (m, 1H), 7.84 (m, 3H), 7.43 (m, 1H), 7.34 (d, 1H), 7.15 (m, 3H), 7.06 (d, 1H), 6.91 (d, 1H), 6.86 (s, 1H), 4.39 (s, 2H), 4.36 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.51 (t, 2H); MS 508 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.[F:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1.O>C(#N)C>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:10][CH2:21][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][F:13])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CO)cc1
Reactant: FCCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(COCc2ccc(OCCF)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
Sodium hydride (0.32 g; 60% in oil) was suspended in 30 ml of dry acetonitrile, and 1.1 g of 4-methoxybenzyl alcohol was added. The mixture was stirred at 50° to 60° C. for 30 minutes. Then, 1.5 g of 4-(2-fluoroethoxy)benzyl chloride was added. The mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water, and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (50 g) column chromatography (developing solvent: a 9:1 mixture of benzene and ethyl acetate) to give 1.6 g of 4-(2-fluoroethoxy)benzyl 4-methoxybenzyl ether.
Reaction SMILES: [N:1]1([C:6]2[C:16]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:30]>>[ClH:30].[ClH:30].[N:1]1([C:6]2[C:16]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(N3CCCC3)c1)OCCNC2
Yield: 30.9 %

Procedure:
A solution of tert-butyl 9-(pyrrolidin-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (90.0 mg, 0.283 mmol) in 4N hydrogen chloride-ethyl acetate (3 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (25.4 mg, 30.9%) as a solid.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Na+].[Na+].[C:14]1([CH2:22]Br)[CH:19]=[CH:18][C:17]([CH2:20]Br)=[CH:16][CH:15]=1>CN(C)C=O>[OH:7][N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:22][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:6]([OH:7])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:16][CH:15]=1
Reactant: CC(C)(C)NO
Reactant: BrCc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)N(O)Cc1ccc(CN(O)C(C)(C)C)cc1
Temperature: 80 °C
Yield: 62.8 %

Procedure:
A suspension of 3.0 g tert-butylhydroxylamine hydrochloride, 5.0 g of anhydrous sodium carbonate and 3.15 g of p-xylylene dibromide in 20 ml of N,N-dimethylformamide is heated at 80° C. under nitrogen for 3 hours. Dilution of the reaction mixture with water followed by crystallization from heptane affords 2.1 g of product as a white solid; m.p. 137°-138° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:9][CH:10]2[C:22](=[O:23])[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:7][N:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CN(C)C=O.C(O)C.CCOCC>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[CH3:3][C:4]1[N:5]([CH2:9][CH:10]2[C:22](=[O:23])[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([S:25]([CH3:24])(=[O:27])=[O:26])[C:13]=3[CH2:12][CH2:11]2)[CH:6]=[CH:7][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nccn1CC1CCc2[nH]c3ccccc3c2C1=O
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2S(C)(=O)=O)C1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.075 g) was added to a solution of 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (0.7 g) in dimethylformamide (10 ml) and the mixture was stirred for 30 min. Methanesulphonyl chloride (0.25 ml) was added and stirring continued at room temperature for 5 h. The resulting solution was partitioned between sodium carbonate (100 ml) and ethyl acetate (3×50 ml). The combined organic layers were washed with water (3×50 ml), dried (Na2SO4), and evaporated in vacuo to give an oil. Purification by flash chromatography (A) gave an oil, which was dissolved in ethanol (10 ml) and added to a solution of maleic acid (0.15 g) in ethanol (5 ml). Addition of dry ether precipitated the title compound (0.7 g) m.p. 141°-142.5°.
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].CN1C(=O)N(C)CCC1.I[CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][C:11]#[C:10][Si:7]([CH3:9])([CH3:8])[CH3:6])=[CH:27][CH:28]=1
Reactant: COc1ccc(CCCCI)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(CCCCC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 124.2 %

Procedure:
12.4 ml (19.8 mmol) of 1.6 M butyllithium in n-hexane was added dropwise at −78° C. to a solution of 1.94 g (2.80 ml, 19.8 mmol) trimethylsilylacetylene and 2.39 ml(19.8 mmol) DMPU in 30 ml THF. After stirring for 1 h at −78° C. a solution of 28.7 g (9.89 mmol) 1-(4-Iodo-butyl)-4-methoxy-benzene in ml THF was added at −78° C. and stirring continued for 30 min. The reaction mixture was allowed to warm to r.t. overnight and then hydrolyzed by a saturated ammonium chloride solution. The water phase was extracted with ether and the combined organic phases were dried over sodium sulphate. Removal of solvents in vacuo gave 3.20 g yellow liquid, which still contained solvent and was used without further purification.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[Br:12][CH2:13][CH3:14]>C(#N)C>[Br-:12].[CH2:13]([N+:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1)[CH3:14]
Reactant: Cc1ccnc2ccccc12
Reactant: CCBr
Solvent: CC#N
Product: CC[n+]1ccc(C)c2ccccc21
Product: [Br-]
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A solution mixture of lepidine (0.5 g, 3.5 mmol) and bromoethane (1.96 g, 18 mmol) in acetonitrile (15 mL) was heated to reflux overnight. After cooling to room temperature, the solvent was removed. The resulting mixture was precipitate from methanol and ethyl acetate to give the desired product 6 (0.81 g) in 92% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.44 (d, J=6 Hz, 1H), 8.60 (d, J=9.2 Hz, 1H), 8.54 (dd, J=8.4 Hz, J=1.2 Hz, 1H), 8.26 (td, J=8.0 Hz, J=1.6 Hz, 1H), 8.09-8.04 (m, 2H), 5.06 (tr, J=7.2 Hz, 2H), 3.00 (s, 3H), 1.58 (t, J=7.2 Hz, 3H). 13C NMR (400 MHz, DMSO-d6) δ 158.4, 148.2, 136.6, 135.1, 129.6, 128.9, 127.2, 122.8, 119.2, 52.5, 19.7, 15.2.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1Cl)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:32][C:33]1([CH3:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.Cl.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN1C(=O)CCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:31])=[N:13][C:14]2[N:15]([N:18]=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:22]=3)[CH:20]=2)[C:16]=1[N:36]1[CH2:37][CH2:38][C:33]([CH3:39])([CH3:32])[CH2:34][CH2:35]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1(C)CCNCC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nc2cc(-c3ccc4c(c3)CCCC4)nn2c(N2CCC(C)(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 29.6 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxy)-2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (40 mg, 0.091 mmol) and 4,4-dimethylpiperidine.HCl (13.55 mg, 0.091 mmol) in NMP (1 mL) was added DIEA (0.047 mL, 0.272 mmol) and the mixture was heated at 50° C. for 2 h. Then, 1N NaOH (0.272 mL, 0.272 mmol) was added to the reaction mixture and the contents were heated at 50° C. for 2 h. The reaction mixture was then filtered and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (13.5 mg, 0.027 mmol, 29.6% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.77-7.71 (m, 2H), 7.19 (s, 1H), 6.95 (s, 1H), 5.80 (s, 1H), 2.91 (s, 2H), 2.84-2.76 (m, 4H), 1.83-1.75 (m, 4H), 1.65-1.58 (m, 2H), 1.56-1.45 (m, 2H), 1.20 (s, 9H), 1.11 (s., 6H). LCMS (M+H)=506.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-methoxybenzene-1-sulfonyl chloride. 1H NMR (DMSO-d6) δ: 3.81 (s, 3H), 7.10 (d, 2H), 7.59 (m, 2H), 7.73 (m, 5H), 7.92 (d, 1H), 8.10 (d, 1H), 9.05 (s, 1H), 10.14 (s, 1H); MS (ES): 442.08 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[OH-].[Na+].[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13]>O>[CH2:10]([N:14]1[C:5](=[O:7])[CH:2]([CH2:3][OH:4])[NH:1][C:15]1=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN=C=O
Reactant: NC(CO)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN1C(=O)NC(CO)C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
DL-Serine (5.0 g) was dissolved in water (25 ml) containing sodium hydroxide (23.8 ml, 2N) and the mixture cooled to 0° C., stirred and n-butyl isocyanate (9.4 g) added. The mixture was stirred at 0° C. for 2 hours then allowed to rise to room temperature overnight, filtered and the filtrate acidified with concentrated hydrochloric acid (50 ml) and heated on a steam-bath for 2 hours. The mixture was cooled and extracted with ether (3×100 ml). Removal of the ether gave an oil which rapidly crystallised and the title product recrystallised from carbon tetrachloride as small cubes, m.p. 93° C. Yield 5.1 g=57%.
Reaction SMILES: ClC1C=C(Cl)C=CC=1CN1C[C@H](C2C=CSC=2)[C@@H](C[N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]2)C1.[OH-].[Na+].[CH3:31]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[CH3:31][O:23][CH2:22][CH:19]1[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: OCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COCC1CCNCC1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 22.2 g (193 mmol) of 4-hydroxymethylpiperidine (Example 8) in 100 mL of CH2Cl2 and 75 mL of a 15% aqueous solution of NaOH was added a solution of 63 g (289 mmol) of Boc2O in 50 ml of CH2Cl2 over a period of 2 h. After stirring for 30 min, the organic layer of the reaction mixture was washed with 15% aqueous NaOH solution and sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=19:1, then 4:1) to give the title compound.
Reaction SMILES: [CH:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O.[C:19]([O-])(=O)[CH3:20].[NH4+:23].[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:3]1[NH:4][C:1]([CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:23][C:11]=1[CH2:10][CH2:19][CH3:20]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1C=O
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCc1nc(C2Cc3ccccc3N2C(=O)OC(C)(C)C)[nH]c1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 255.2 %

Procedure:
Intermediate (12) (0.00101 mole), 2-3-hexanedione (0.004 mole), and ammonium acetate (0.025 mole) were combined in acetic acid (4 ml), and immediately placed on a steam bath for 15 minutes. After 2 hours at room temperature, the reaction was poured into ice water (100 ml), basified with 3N NaOH, and extracted with diethylether (twice). The organic phases were combined, dried, filtered, and concentrated. The residue was taken up in diethylether, concentrated and then purified by prep LC, yielding 0.440 g of 1,1-dimethylethyl 2,3-dihydro-2-(5-methyl-4-propyl-1H-imidazol-2-yl)-1H-indole-1-carboxylate (compound 99).
Reaction SMILES: COC1C=CC(C2N[C:13](=[O:15])[C:12]3[CH:16]=[CH:17][S:18][C:11]=3[CH:10]=2)=CC=1.P(Cl)(Cl)(Cl)=[O:20]>>[CH3:10][C:11]1[S:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2cc3sccc3c(=O)[nH]2)cc1
Product: Cc1sccc1C(=O)O
Temperature: 120 °C
Yield: 131.3 %

Procedure:
6-(4-Methoxyphenyl)-5H-thieno[3,2-c]pyridin-4-one (9.1 g) was added to phosphorus oxychloride (90 g), and the mixture was heated at 120° C. for 3 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporate, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a white powder (6.6 g, yield; 73%).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[S:19]1[CH:23]=[C:22]([C:24]([O-])=[O:25])[N:21]=[C:20]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:24]([C:22]3[N:21]=[C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:19][CH:23]=3)=[O:25])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CCOC(=O)c1nc(C(=O)[O-])cs1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 82 %

Procedure:
(S)-ethyl 4-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl-carbamoyl)thiazole-2-carboxylate was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (540 mg, 2.071 mmol) and 2,4-thiazoledicarboxylic acid, 2-ethyl ester (500 mg, 2.485 mmol). Yield 82%. 1H-NMR (400 MHz; DMSO3): δ 1.18 (d, 3H), 1.35 (t, 3H), 4.35 (dd, 1H), 4.39-4.57 (m, 4H), 6.94 (d, 1H), 7.84 (d, 1H), 7.95 (m, 2H), 8.02 (m, 1H), 8.55 (s, 1H), 8.61 (d, 1H).
Reaction SMILES: CO[C:3](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=2)[NH:14][C:13]1=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[N:25]1([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([NH:36]/[C:3](=[C:12]3\[C:13](=[O:24])[NH:14][C:15]4[C:20]\3=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=4)/[C:4]3[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=3)=[CH:37][CH:38]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccc(OC)cc1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Product: COc1ccc(/C(Nc2ccc(CN3CCCCC3)cc2)=C2/C(=O)Nc3ccc([N+](=O)[O-])cc32)cc1

Procedure:
Prepared analogously to Example 39d from 3-[1-methoxy-1-(4-methoxyphenyl)-methylidene]-5-nitro-2-indolinone and 4-piperidinomethyl-aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].Cl.Cl[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]Cl>C1(C)C(C)=CC=CC=1>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:12][CH:13]3[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]3)[CH2:20]1)[CH2:18]2)=[O:8]
Reactant: ClCCNCCCl
Reactant: Nc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCNCC2)ccc1Cl
Temperature: 150 °C
Yield: 74 %

Procedure:
To a solution of 5-amino-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (1.00 g, Example 4b) in xylene (20 ml) was added bis-(2-chloroethyl)amine hydrochloride salt (0.620 g). The mixture was heated at 150° C. for 12 h (a dark solution is obtained). The cold solution was washed with 2M HCl, the aqueous layer washed with ethyl acetate then basified with sodium bicarbonate and extracted twice with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a foam. The crude material was purified on silica gel (0-10% ethanol/dichloromethane), to afford the title compound as a white solid (0.90 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([CH3:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([CH3:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[O:27][CH:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1c2ccccc2c(-c2cc(Br)c(O)c(Br)c2)c2c1sc1ccccc12
Solvent: ClC(Cl)Cl
Product: Cc1c2ccccc2c(-c2cc(Br)c(OC(Cc3ccccc3)C(=O)O)c(Br)c2)c2c1sc1ccccc12

Procedure:
Prepared from 2,6-dibromo-4-(6-methyl-benzo[b]naphtho[2,3-d]thiophen- 11-yl)-phenol (Example 62) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: mp 117-122° C.: [a]D25=+34.13° (9.963 mg/mL CHCl3); NMR (DMSO-d6): δ8.17 (d, J=8 Hz, 1 H), 7.81 (d, J=8 Hz, 1 H), 7.63-7.58 (m, 1 H), 7.57 (dd, J=6, 2 Hz, 2 H), 7.52-7.46 (m, 2 H), 7.42-7.38 (m, 3 H), 7.37-7.28 (m, 3 H), 7.16-7.10 (dt, J=1, 6 Hz, 1 H), 6.76 (d, J=8 Hz, 1 H), 5.45 (t, J=7 Hz, 1 H, CH), 3.59 (d, J=7 Hz, 2 H), 2.98 (s, 3 H); MS (EI): [M+], 643.6 (20%), 644.4 (50%), 645.5 (100%) 647.7 (30%); Anal. Calc. for C32H22Br2O3S: C, 59.46, H, 3.43, N, 0.00. Found: C, 59.34, H, 3.24, N, 0.04.
Reaction SMILES: [CH2:1]1[CH:23]2[NH:24][CH:3]([CH:4](C3C=CC(C(O)=O)=CC=3)[CH:5]3[NH:9][CH:8]([CH:10](C4C=CC(C(O)=O)=CC=4)[CH:11]4[NH:15][CH:14]([CH:16](C5C=CC(C(O)=O)=CC=5)[CH:17]5[NH:21][CH:20]([CH:22]2C2C=CC(C(O)=[O:32])=CC=2)[CH:19]=[CH:18]5)[CH2:13][CH2:12]4)[CH:7]=[CH:6]3)[CH2:2]1.[O-2:61].[O-2].[Ti+4:63].C1(C)C(C)=CC=CC=1>C(O)CCC>[C:5]12[CH:4]=[C:3]3[N:24]=[C:23]([CH:1]=[CH:2]3)[CH:22]=[C:20]3[NH:21][C:17]([CH:18]=[CH:19]3)=[CH:16][C:14]3=[N:15][C:11]([CH:12]=[CH:13]3)=[CH:10][C:8]([NH:9]1)=[CH:7][CH:6]=2.[O-2:32].[Ti+4:63].[O-2:61]
Reactant: O=C(O)c1ccc(C2C3C=CC(N3)C(c3ccc(C(=O)O)cc3)C3CCC(N3)C(c3ccc(C(=O)O)cc3)C3C=CC(N3)C(c3ccc(C(=O)O)cc3)C3CCC2N3)cc1
Agent: [Ti+4]
Agent: [O-2]
Solvent: CCCCO
Solvent: Cc1ccccc1C
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
An invented undercoat layer dispersion was prepared as follows: a porphine/titanium oxide/phenolic resin/melamine resin dispersion was prepared by ball milling 0.25 grams of meso-Tetraphenylporphine-4,4′,4″,4′″-tetracarboxylic acid (commercially available from Frontier Scientific, Inc., Logan, Utah), 15 grams of titanium dioxide (MT-150W, Tayca Company), 8 grams of the phenolic resin (VARCUM 29159, OxyChem Company, Mw of about 3,600, viscosity of about 200 cps) and 7.5 grams of the melamine resin (CYMEL 323, CYTEC) in 7.5 grams of 1-butanol, and 7.5 grams of xylene with 120 grams of 1 millimeter diameter sized ZrO2 beads for 5 days. The resulting titanium dioxide dispersion was filtered with a 20 micrometer pore size nylon cloth, and then the filtrate was measured with HORIBA CAPA 700 Particle Size Analyzer, and there was obtained a median TiO2 particle size of 50 nanometers in diameter and a TiO2 particle surface area of 30 m2/gram with reference to the above Porphine/TiO2/VARCUM/CYMEL dispersion. 0.5 grams of methyl ethyl ketone were added into the dispersion to obtain the coating dispersion. An aluminum drum, cleaned with detergent and rinsed with deionized water, was then coated with the above generated coating dispersion, and subsequently dried at 160° C. for 40 minutes, which resulted in the TUC8 layer deposited on the aluminum and comprised of TiO2/VARCUM/CYMEL with a weight ratio of about 60/16/24 and a thickness of 5.5 microns.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4](F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]2)[CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Br)cc1N1CCN(CCO)CC1
Temperature: 110 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a suspension of 4-bromo-2-fluorobenzaldehyde (281 μL, 2.37 mmol) and potassium carbonate (328 mg, 2.37 mmol) in 5 mL of dry N,N-dimethylformamide was added 4-(2-hydroxyethyl)piperazine (463 mg, 3.56 mmol) at room temperature. After being stirred at 110° C. for 12 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (chloroform/methanol=98/2 to 90/10) to obtain the title compound as a pale yellow powder (364 mg, 49%).