Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])[NH:7][CH2:6][CH2:5]2
Reactant: CN(C)CCOc1cc2[nH]ccc2cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CCOc1cc2c(cc1Cl)CCN2
Reaction time: 1 h
Yield: 10.9 %

Procedure:
5-Chloro-6-(2-dimethylaminoethoxy)-1H-indole (D8, 0.2 g, 0.008 mol) in glacial acetic acid (5 ml) was treated with sodium cyanoborohydride (0.25 g, 0.004 mol ) at room temperature with stirring for 1 h. The mixture was diluted with water and basified with 10% aq NaOH. The product was extracted into CH2Cl2, and the combined extracts dried (Na2SO4) and concentrated in vacuo to give the title compound as a brown oil (0.21 g, 100%)
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][N:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:14]=[C:13]([CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[CH:12]=[CH:11][N:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cc(CO)ccn2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cc(COS(C)(=O)=O)ccn2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-4-yl]-methanol (530 mg, 2.72 mmol) in dry CH2Cl2 (5 mL) was treated at 0° C. with Et3N (0.50 mL, 3.56 mmol) followed by DMAP (34 mg, 0.27 mmol) and Ms-Cl (0.27 mL, 3.46 mmol). After stirring at rt for 2 h, the reaction was quenched with water (5 mL). The org. layer was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a light brown oil. TLC: rf (1:2 hept-EA)=0.36.
Reaction SMILES: [CH:1]1([N:7]([CH:30]([CH3:32])[CH3:31])[C:8](=[O:29])[C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.S(=O)(=O)(O)O.[Pd].C(OCC)(=O)C>[CH:1]1([N:7]([CH:30]([CH3:32])[CH3:31])[C:8](=[O:29])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(O)c2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(Cc2ccc(C(=O)N(C(C)C)C3CCCCC3)cc2)cc(OC)c1OC

Procedure:
The compound prepared in Example 14 (800 mg, 1.81 mmol) in ethyl alcohol (20 mL) containing concentrated sulfuric acid (4 drops) was hydrogenated at 60 psi and room temperature using 5% Pd/C as catalyst. The catalyst was filtered and the filtrate concentrated in vacuo to give the crude product as an oil. The crude product was dissolved in ethyl acetate and washed twice with aqueous NaHCO3 solution and then with saturated aqueous NaCl solution. After drying (Na2SO4), the organic layer was filtered and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[S:18]([O:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:37][C:34]2[CH:33]=[CH:32][C:31]([CH2:30][CH2:29][O:28][S:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=4)(=[O:19])=[O:20])=[CH:36][CH:35]=2)=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(O)cc2)cc1
Reactant: O=C(Cl)c1c2ccccc2nc2ccccc12
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(OC(=O)c3c4ccccc4nc4ccccc34)cc2)cc1
Yield: 54.7 %

Procedure:
In 30 ml of pyridine, 2.4 g of the compound (2) obtained in Example 2 were dissolved. Under ice cooling and stirring, 2.9 g of the compound (1) obtained in Example 1 were added in small portions. Subsequent to stirring at room temperature for 2 hours, the pyridine was distilled off under reduced pressure. CHCl3 was added further, and distillation was repeated twice under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (eluent: CHCl3), whereby 2.7 g of the compound (3) were obtained (yield: 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][Cl:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:13][CH2:14][Cl:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(OCCCl)c1
Temperature: 80 °C

Procedure:
A mixture of 2-chloro-5-nitrophenol (4 g, 23 mmol), 1-bromo-2-chloroethane (9 mL, 115 mmol), and K2CO3 (8 g, 58 mmol) in DMF (50 mL) was heated at 80° C. for 18 h. The mixture was diluted with water and extracted several times with EtOAc. The combined organic layers were washed with 1N NaOH (aq) and concentrated in vacuo to yield the title compound and a bromo adduct contaminant.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:14]COC)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18]O>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:18])=[O:10])=[C:7]([OH:14])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cc(C(C)(C)C)ccc1C(=O)O
Reactant: CO
Product: COC(=O)c1ccc(C(C)(C)C)cc1O
Temperature: 0 °C
Yield: 87 %

Procedure:
A dry reaction flask equipped with a stirring bar and a rubber septum was charged with 4-tert-butyl-2-(methoxymethoxy)benzoic acid (11.9 g, 50 mmol) and MeOH (166 mL). The solution was cooled to 0° C. and dry HCl gas was bubbled into the reaction. The reaction color changed from faint yellow to peach and again back to faint yellow. The reaction mixture was refluxed for 18 h, cooled to room temperature, and the solvent was removed. The resulting thick oil was diluted with CH2Cl2 (100 mL) and washed with H2O (100 mL) and 5% aqueous NaHCO3 solution (2×50 mL). The organic solution was dried (Na2 SO4) and the solvent was removed to obtain the requisite compound (9.10 g, 87%) as a colorless liquid, TLC Rf: 0.77 (10% EtOAc/n-hexanes).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[S:6]1[CH:10]=[CH:9][C:8]2C(=O)CC[CH2:14][C:7]1=2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:4]=[C:3]1[C:8]2[CH:9]=[CH:10][S:6][C:7]=2[CH2:14][CH2:1][CH2:2]1
Reactant: O=C1CCCc2sccc21
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCCc2sccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes; 105.3 ml) was added dropwise under nitrogen at 0° C. over 30 minutes to a stirred solution of methyltriphenyl-phosphonium bromide (75.16 g) in tetrahydrofuran (250 ml), then the mixture was stirred at ambient temperature for 90 minutes. A solution of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (20 g) in tetrahydrofuran (200 ml) was added, the mixture was stirred at ambient temperature for 1 hour, then it was heated under reflux for 24 hours and cooled to ambient temperature. The solvents were removed in vacuo and the residue was purified by flash chromatography over silica using a 98:2 mixture of petroleum ether (b.p. 60-80° C.) and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 4-methylene-4,5,6,7-tetrahydrobenzo[b]thiophene (8.8 g) as a yellow oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH2:54][CH2:55]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:55][CH2:54][O:53][C:52]2[CH:58]=[CH:59][CH:60]=[CH:61][C:51]=2[O:50][CH3:49])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccccc1OCCCO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCOc4ccccc4OC)cc3)c2cc1OC
Temperature: 25 °C
Yield: 74.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (72 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (109 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-methoxyphenoxy)-1-propanol (66 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (91 mg, yield 69%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29].[C:37]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46](O)=O)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].CCN(C(C)C)C(C)C>CN(C)C=O.C(O)(=O)C>[C:40]([O:39][C:37]([N:44]1[CH2:51][CH2:50][CH2:49][C@H:45]1[C:46]1[NH:25][C:26]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=[CH:34][C:35]=2[N:36]=1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1cccc2nc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]c12
Temperature: 60 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
HATU (10.66 g, 28.0 mmol) was added in one portion to a stirred solution of methyl 2,3-diaminobenzoate (4.1 g, 24.7 mmol), N-Boc-L-proline (5.49 g, 25.5 mmol), and Hunig's base (4.9 mL, 28.0 mmol) in dimethylformamide (50 mL). The reaction mixture was stirred 3 h and solvent removed in vacuo, and the residue was diluted with ethyl acetate, washed with 0.1N HCl, sat'd NaHCO3, brine, and dried (Na2SO4). Concentration gave a reddish brown viscous oil which was taken up in glacial acetic acid (60 mL) and heated at 60° C. for 16 h. The solvent was removed in vacuo, and the residue was diluted with ethyl acetate, washed with sat'd NaHCO3 soln., brine, and dried (Na2SO4). Concentration gave a residue that was divided into two lots, and each lot pre-adsorbed onto SiO2 (dichloromethane), applied to a 40 M Biotage SiO2 column, and eluted by gradient 10%-100% B (1440 mL); A=hexanes; B=ethyl acetate to give J.33 (S)-methyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazole-7-carboxylate 7.05 g (83%) as a reddish oil. 1H NMR (500 MHz, DMSO-d6) δ: 7.86 (d, J=7.9 Hz, 1H), 7.78 (t, J=5 Hz, 1H), 7.28-7.24 (m, 1H), 5.20-5.11 (m, 1H), 3.95 (s, 3H), 3.60-3.52 (m, 1H), 3.43-3.38 (m, 1H), 2.33-2.22 (m, 1H), 2.15-2.0 (m, 2H), 1.91-1.86 (m, 1H), 1.40/1.05 (s, 9H). LC (Cond.-D2): RT=1.86 min; LC/MS: Anal. Calcd. for [M+H]+ C18H24N3O4: 346.18; found 346.26; HRMS: Anal. Calcd. for [M+H]+ C18H24N3O4: 346.1767; found: 346.1776.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:33])[C:16](=[O:32])[C:17]([CH3:31])=[C:18]([NH:19][C:20]3[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[C:13]=2[C:12](=[O:34])[N:11]([CH3:35])[C:10]1=[O:36].CC(C)([O-])C.[K+].CO.C(O)(=O)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:14]1[N:15]([CH3:33])[C:16](=[O:32])[C:17]([CH3:31])=[C:18]2[C:13]=1[C:12](=[O:34])[N:11]([CH3:35])[C:10](=[O:36])[N:19]2[C:20]1[CH:21]=[C:22]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(Nc2cccc(NS(C)(=O)=O)c2)c2c(=O)n(C)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1c(=O)n(C)c(Nc2ccc(I)cc2F)c2c(=O)n(C)c(=O)n(-c3cccc(NS(C)(=O)=O)c3)c12
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Under ice-cooling, to a suspension of N-{3-[1-(2-fluoro-4-iodophenyl)-3,6,8-trimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}methanesulfonamide 71 (3.10 g) obtained in Step 7 in tetrahydrofuran (31.0 ml) was added dropwise a mixture of potassium t-butoxide (1.33 g), methanol (0.482 ml) and tetrahydrofuran (15.5 ml), and the mixture was stirred under ice-cooling for 2 hrs. Acetic acid (1.36 ml) was added, the mixture was allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was concentrated, methanol/water [1:2 (volume ratio), 45.0 ml] was added, and the mixture was further stirred at room temperature for 1 hr. The crystals were collected by filtration and dried to give N-{3-[5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}methanesulfonamide 72 (3.01 g, yield 97%) as a pale-gray solid.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[ClH:19].[N:20]1([CH2:26][CH2:27][NH:28][S:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Reactant: NCCN1CCCCC1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCCCC3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 84 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride is reacted with (2-piperidin-1-yl)ethylamine as described in Steps 5 and 6, Example 24 to give the title compound as a solid (84% yield). LC/MS: RT 2.02 min; m/e 394 (M+H).
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:16]1[C:4](=[O:15])[C:5]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[CH:6][NH:7]1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: NNc1ccccn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1ccccn1

Procedure:
250 mg (1.19 mmol) of the compound from Example 3A, 108 mg (0.99 mmol) 2-hydrazinopyridine and 23 mg (99 μmol) camphor-10-sulfonic acid are dissolved in 5 ml anhydrous ethanol and the mixture is heated under reflux overnight. In each case 108 mg (0.99 mmol) 2-hydrazinopyridine are added again a total of four times and the mixture is heated further under reflux until the conversion of the compound from Example 3A is complete. After cooling, the reaction mixture is purified by preparative HPLC several times (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid) and 6 mg (2% of th.) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7]O)[CH2:2][CH2:3][CH3:4].[C:9]([OH:16])(=[O:15])[CH2:10][CH2:11][C:12]([CH3:14])=[O:13].CCCCCCCC(O[Sn](OC(CCCCCCC)=O)(CCCC)CCCC)=O>C1(C)C(C)=CC=CC=1>[C:9]([O:16][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:15])[CH2:10][CH2:11][C:12]([CH3:14])=[O:13]
Reactant: CC(=O)CCC(=O)O
Reactant: CCCCOCCO
Agent: CCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCC
Solvent: Cc1ccccc1C
Product: CCCCOCCOC(=O)CCC(C)=O

Procedure:
2-Butoxyethanol (Butyl Cellosolve) 354g (3 mol), 232g (2mol) levulinic acid and 1.5g dibutyl tin dioctoate were heated with a xylene azeotrope for 24 hours 151°-177° to AN 2.3 while collecting 42g water. Product was washed with sat. NaHCO3 and water, dried with anhy. MgSO4 and distilled. Ester product was collected in fr 2 and 3, 120°-131° 1 mm. Yield was 349g, 81%, 96% ester product by gc.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1>>[CH:24]1([C:27]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:12]2)=[O:28])[CH2:26][CH2:25]1
Reactant: O=C(O)C1CC1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3CC3)C2)cc1

Procedure:
68 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 19 mg (0.22 mmol, 1.1 eq.) of cyclopropanecarboxylic acid were reacted according to General Method 1. Yield: 38 mg (50% of theory)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[NH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12]([NH:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34])[N:13]=2)=[C:4]([CH3:30])[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Reactant: NC(CO)CO
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1ccccc1F

Procedure:
The product of Example 59, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(4-fluoro-2-methyl-phenyl)-8-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 2.24 (s, 3H), 2.68 (br s, 2H), 3.42 (m, 1H), 3.61 (m, 4H), 6.30 (br s, 1H), 6.38 (d, 1H, J=9.7 Hz), 7.02 (m, 21H), 7.27 (m, 5H), 7.46 (m, 1H). LC MS (m/e)=439 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([NH2:26])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28](=O)[C:29](=O)[CH3:30].[C:33]1([CH3:43])[CH:38]=[CH:37][C:36](S(O)(=O)=O)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[N:12]([N:26]=[C:28]([C:29](=[N:26][N:12]3[C:43]([C:33]4[CH:38]=[CH:37][C:36]([C:16]([CH3:21])([CH3:17])[CH3:13])=[CH:35][CH:34]=4)=[CH:14][CH:15]=[C:11]3[C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH3:30])[CH3:27])[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)=[CH:15][CH:14]=2)=[CH:21][CH:20]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)C(C)=O
Reactant: CC(C)(C)c1ccc(-c2ccc(-c3ccc(C(C)(C)C)cc3)n2N)cc1
Solvent: Cc1ccccc1
Product: CC(=Nn1c(-c2ccc(C(C)(C)C)cc2)ccc1-c1ccc(C(C)(C)C)cc1)C(C)=Nn1c(-c2ccc(C(C)(C)C)cc2)ccc1-c1ccc(C(C)(C)C)cc1
Temperature: 80 °C
Yield: 539.2 %

Procedure:
A solution of 2,5-bis-(4-tert-butyl-phenyl)-pyrrol-1-ylamine (174 mg, 0.502 mmol) in toluene (4.5 mL) was treated with butanedione (19.7 μL, 0.225 mmol) and p-toluene sulfonic acid (5.2 mg). The resulting solution was heated to 80° C. in an oil bath under Ar overnight. The solution was cooled to rt and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 33% CH2Cl2/heptane) to afford 2,3-bis(2,5-bis(4-tert-butylphenyl)-pyrrol-1-ylimino)-butane (121 mg, 72%): 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.33 (s, 36H), 1.69 (s, 6H), 6.39 (s, 4H), 7.33-7.39 (m, 16H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:25])[C@@H:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1)=[O:29]>C(#N)C>[Br-:26].[C:37]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([C:28](=[O:29])[CH2:27][N+:1]23[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]2)[C@@H:3]([O:9][C:10](=[O:25])[C@@H:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:2]3)=[CH:31][CH:32]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)[C@H](Nc1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Product: [Br-]

Procedure:
A mixture (R)-((R)-quinuclidin-3-yl) 2-phenyl-2-(phenylamino)acetate (Diastereoisomer 1 of C2) (80.0 mg, 0.24 mmol) and N-(4-(2-bromoacetyl)phenyl)acetamide (60.9 mg, 0.24 mmol) in acetonitrile (2 mL) is heated in a microwave oven at 100° C. for 1 hour (UPLC-MS monitoring: complete conversion). The title compound is isolated by suction filtration and washed with Et2O (98.2 mg, 81% yield, off-white solid, bromide salt, single diastereoisomers).
Reaction SMILES: C[C@@H]([C@@H]1[C@@]2(C)CCC3[C@@]4(C)CCC(OC([Cl:29])=O)CC4=CCC3C2CC1)CCCC(C)C.[CH2:32]([O:39][CH:40]([CH2:43][OH:44])[CH2:41]O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(Cl)Cl.N1C=CC=CC=1.O>[CH2:32]([O:39][CH:40]([CH2:43][OH:44])[CH2:41][Cl:29])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: OCC(CCl)OCc1ccccc1
Yield: 135.4 %

Procedure:
A solution of 10.2 g of cholesteryl chloroformate in 130 ml of methylene chloride is treated under argon while stirring with 4.6 g of 2-O-benzylglycerol in 120 ml of methylene chloride and 2 ml of pyridine, taken up in 500 ml of water and 50 ml of 1N HCl after 1 hour and extracted with methylene chloride. The organic phase is dried and concentrated at 50° C. After chromatography over SiO2 with n-hexane:ether (1:1) there are obtained 6.17 g of (RS)-2-(benzyloxy)-3-hydroxypropyl chloride 5-en-3β-ylcarbonate, MS: 595 (M+H+), the starting material of Example 13.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[CH:21]=[CH:22][S:23][C:14]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[CH:21]=[CH:22][S:23][C:14]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc2ccsc2c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A mixture of 2,4-dichloroaniline (333.8 mg, 2.06 mmol) and 60% sodium hydride (82.4 mg, 2.06 mmol) in 10 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol) is added. The resulting reaction mixture is heated at reflux for 7 hours, cooled to room temperature, and concentrated in vacuo. The residue is treated with water for 1 hour. The precipitate is filtered, washed with water, and air dried. The resultant solid is purified by flash column chromatography eluting with a gradient of 1% ethyl acetate in hexane to 8% ethyl acetate in hexane to provide 173.1 mg of 7-[(2,4-dichlorophenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 198-200° C.; 1H NMR (DMSO-d6) δ 7.47 (d, J=4 Hz, 1H), 7.54 (dd, J=6, 2 Hz, 1H), 7.59 (d, J=6 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 8.12 (d, J=4 Hz, 1H), 8.61 (s, 1H), 9.67 (s, 1H); MS 318.1, 320.2 (M+H)+.