Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:33][C:30]4([CH2:29][CH2:28][O:27][CH3:26])[CH2:32][CH2:31]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: COCCC1(N)CC1
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4OC)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 159 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine 1H NMR (400 MHz, DMSO-d6) δ 0.58-0.74 (m, 4 H) 1.80 (t, J=6.9 Hz, 2 H) 3.14 (s, 4 H) 3.39 (t, J=7.1 Hz, 2 H) 3.89 (s, 3 H) 7.32-7.44 (m, 2 H) 8.27-8.35 (m, 2 H) 8.42 (d, J=8.8 Hz, 1 H) 8.57 (d, J=7.6 Hz, 1 H) 8.76 (s, 1 H) 8.80 (d, J=1.8 Hz, 1 H). MS m/z [M+H]+ 434.5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:21]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])(=[O:19])=[O:18])=[O:22])[N:3]=1
Reactant: Cc1nc(C)nc(N)n1
Reactant: Cc1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: Cc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C)n1

Procedure:
To 12.3 g 2-amino-4,6-dimethyl-1,3,5-triazine in 250 ml of dry acetonitrile was added, with stirring, 19.7 g of 2-methylbenzenesulfonyl isocyanate at a rate designed to avoid excessive heating of the reaction mixture. Stirring was continued until the desired product crystallized. The product was removed by filtration, washed with a small amount of ethyl ether and dried. The resulting product, N-[(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-methylbenzenesulfonamide, melted at 141°-145° C.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH3:26][N:27]([CH3:41])[C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.Cl>CN(C=O)C>[CH3:26][N:27]([CH3:41])[C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH:31]([CH:2]=[O:3])[CH2:30][CH2:29]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccccc2)CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under argon, methoxymethyltriphenylphosphonium chloride (6.3 g, 18.4 mmol) was dissolved in DMF (25 ml), and sodium hydride (60 wt. % in mineral oil, 737 mg, 18.4 mmol) was added. A solution of 4-dimethylamino-4-phenylcyclohexanone (2.0 g, 9.2 mmol) in 25 ml of DMF was added dropwise over 30 min and the suspension was stirred for 3 d at RT. For the work-up, the suspension was poured slowly into 2 M HCl (50 ml) cooled with ice-water, stirred at RT for 2 h and then extracted with diethyl ether (5×25 ml) and EE (6×20 ml). The aqueous phase was then brought to pH 10-11 with 1 M NaOH and extracted with EE (5×20 ml). The combined extracts were dried with sodium sulfate, filtered and concentrated. The residue was 4-dimethylamino-4-phenylcyclohexanecarbaldehyde (2.0 g of brown oil) in a diastereoisomer ratio of 55:45 (1H NMR).
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:1]=[C:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1O)C2
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)C12CC3CC(CC(C3)C1=O)C2

Procedure:
To a solution of 100 ml of 2-hydroxyadamantane dissolved in 250 ml pyridine is added 137.9 g of trifluoroacetic anhydride dropwise, and the reaction mixture is stirred overnight. The reaction mixture is poured over ice then diluted to 1.0 liter with water and extracted three times with 500 ml of diethyl ether. The combined diethyl ether extracts are washed with 5% hydrochloric acid until the wash is acidic then washed once with 5% sodium bicarbonate solution and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 2-adamantyl trifluoroacetate as an oil. 50 Grams of 2-adamantyl trifluoroacetate are dissoled in 500 ml of hexane and photolyzed (254 nm) for 4 days. The solvent is removed under reduced pressure and the oily residue is placed in a low pressure column and eluted with dichloroethane. The starting material is the first major component eluted. The second major component is the product, 1-trifluoroacetyl-2-hydroxyadamantane which is crystallized from pentane. To 100 ml of 10% sodium hydroxide solution is added 13.0 g of 1-trifluoroacetyl-2-hydroxyadamantane. The reaction mixture is heated for 15 minutes on a steam bath then diluted to 200 ml with water and washed two times with 150 ml of diethyl ether. The aqueous solution is acidified with concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and dried in a steam cabinet to give 2-hydroxy-1-adamantanecarboxylic acid. 6.7 Grams of 2-hydroxy-1-adamantanecarboxylic acid are dissolved in 50 ml of acetone and enough 8 N Jones Reagent (chromic anhydride in dilute sulfuric acid) is added to retain a red color for 1 minute. Isopropyl alconhol is added to destroy any excess Jones reagent and the solvent is removed under reduced pressure. The residue is diluted with water, collected by filtration and washed with water then suction dried to give 2-keto-1-adamantanecarboxylic acid. 4.7 Grams of 2-keto-1-adamantanecarboxylic acid is dissolved in 75 ml of ethanol and hydrogenated over platinum oxide in the presence of ammonia gas under 60 psi of pressure at room temperature. The solvent is removed under reduced pressure. 15 ml of water is added to the residue and removed under reduced pressure. This step is repeated with another 15 ml of water then the residue is dried at 100° C. under reduced pressure for 1 hour to give 2-amino-1-adamantanecarboxylic acid which is represented by the following structure ##STR45##
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21]>CN(C=O)C>[CH:20]([C:19]1[CH:18]=[C:17]([CH:24]=[CH:23][CH:22]=1)[O:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[O:21]
Reactant: N#Cc1ccc(F)cc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cccc(C=O)c2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 1.2 g portion of 4-fluorobenzonitrile and 1.0 g of potassium carbonate were added to 25 ml DMF solution of 1.2 g of 3-hydroxybenzaldehyde and stirred overnight with heating at 100° C. The reaction solution was poured into ice water, and then work-up and purification were carried out in the standard method to obtain 1.6 g of 4-(3-formylphenoxy)benzonitrile as an oily substance. EI: 223.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32]([O:33][CH3:34])=[CH:31][C:12]2[C:13](=[O:30])[N:14]3[CH2:29][CH2:28][CH2:27][C@H:15]3[C@H:16](O)[N:17](C(OCC(Cl)(Cl)Cl)=O)[C:11]=2[C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:32]([O:33][CH3:34])=[CH:31][C:12]2[C:13](=[O:30])[N:14]3[CH2:29][CH2:28][CH2:27][CH:15]3[CH:16]=[N:17][C:11]=2[C:10]=1[O:35][CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(c(OC)c1OCc1ccccc1)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1OCc1ccccc1)N=CC1CCCN1C2=O
Reaction time: 3.5 h
Yield: 68.4 %

Procedure:
10% Cd/Pb couple (1.2 g; 10 mmol Cd) was added to a rapidly stirring solution of 142 (1.08 g; 1.9 mmol) in a mixture of THF (15 mL) and 1N NH4OAc (15 mL). After 3.5 h, TLC revealed that reaction was still incomplete and more 10% Cd/Pb couple (500 mg) was added. After a further 1 hour the reaction mixture was diluted with EtOAc (150 mL). The solution was dried over anhydrous MgSO4 and the solids were filtered and rinsed with EtOAc (50 mL). Removal of excess solvent yielded the product as a yellow glass (0.48 g, 1.3 mmol, 68%). H1NMR (270 MHz, CDCl3) δ 7.73 (d, 1H, J=4.4 Hz), 7.36 (s, 2H), 7.31 (s, 2H), 7.11 (s, 1H), 7.08 (s, 1H), 5.12 (br s, 2H), 3.98-3.42 (m, 9H), 2.38-2.29 (m, 2H), 2.23-1.83 (m, 2H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:16]Br.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][C:15]([O:20][CH3:21])([O:18][CH3:19])[CH2:14]2)=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: COC(CBr)(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1(OC)CC(C#N)(c2ccc(Br)cc2)C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
To a suspension of NaH (0.733 g, 18.32 mmol, 60% in mineral oil) in DMF (14 mL) was added 2-(4-bromophenyl)acetonitrile (1.796 g, 9.16 mmol) followed by 1,3-dibromo-2,2-dimethoxypropane (2.0 g, 7.64 mmol) and the reaction mixture was heated to 60° C. and stirred for 12 h. The reaction mixture was cooled to RT, poured into water (150 mL) and extracted with EtOAc (3×40 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by silica gel chromatography (24 g REDISEP® column, eluting with 5% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 314A as a white solid (2 g, 88%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.68-7.57 (m, 2H), 7.46-7.40 (m, 2H), 3.18 (s, 3H), 3.08 (s, 1H), 3.07 (s, 3H), 3.05-3.02 (m, 1H), 2.74-2.71 (m, 1H), 2.70-2.67 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([OH:30])[C@H:23]1[O:27][CH2:26][C@H:25]([OH:28])[C@H:24]1[OH:29])=[O:19].CCCCCCCCCCCC(OCC(O)[C@H]1OC[C@H](O)[C@H]1O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([OH:30])[C@H:23]1[O:27][CH2:26][C@H:25]([OH:28])[C@H:24]1[OH:29])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Agent: CCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O

Procedure:
sorbitan monooleate; and sorbitan monolaurate
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([C:10](=[O:21])[NH:11][CH:12]2[CH2:14][CH:13]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][N:6]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])=[O:4].[OH-].[Na+]>C1COCC1>[CH2:25]([O:24][C:22]([N:6]1[CH2:7][CH:8]([C:10](=[O:21])[NH:11][CH:12]2[CH2:14][CH:13]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)C1CC(C(=O)NC2CC2c2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC1CC1c1ccccc1)C1CC(C(=O)O)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 4-(2-Phenyl-cyclopropylcarbamoyl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (422 mg, 1 mmol) in THF (2 mL) was added 1 N NaOH (1.5 mL) at 0° C. with stirring. After 30 min at 0° C. and 16 h at room temperature, the reaction mixture was concentrated and treated with EtOAc and 6 N HCl (5 mL). The organic layer was dried over MgSO4 and concentrated. The residue was purified by a silica gel column using CH2Cl2/MeOH (95:5) as eluant to yield the desired compound as a colorless oil (343 mg, 84%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24]>C1(C)C(C)=CC=CC=1>[Cl:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:24]
Reactant: O=C(Cl)CCCCCCl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: Cc1ccccc1C
Product: O=C1Nc2cccnc2N(C(=O)CCCCCCl)c2ccccc21

Procedure:
A solution of 5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one and 6-chloro-caproyl chloride in xylene was reacted to obtain 11-(6-chloro-caproyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 128°-130° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>C1(C)C=CC=CC=1>[C:24]1([O:23][C:21](=[O:22])[N:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:10][CH:9]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCc1ccc(CNCCCCCCO)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CN(CCCCCCO)C(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.1 %

Procedure:
To a stirred solution of 7.26 g of 6-[[(4-butylphenyl)methyl]amino]-1-hexanol in 50 ml of toluene was added a solution of 2.16 g of phenyl chloroformate in 20 ml of toluene, with the immediate precipitation of a white solid. The resulting mixture was stirred at room temperature for 24 hours. The mixture was filtered, and the filter was washed with toluene. The combined filtrate and wash was evaporated in vacuo and gave a colorless oil. The oil was Kugelrohr distilled and gave 3.5 g of the desired product in 66% yield as a colorless oil, bp 180°-195° C./0.06 mm of mercury.
Reaction SMILES: [C:1]([CH:3]([CH:16]([C:28]([NH2:30])=[O:29])[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)#[N:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([CH:3]([CH:16]([C:28]([NH2:30])=[O:29])[C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)#[N:2]
Reactant: CCOC(=O)c1ccc(C(C(N)=O)C(C#N)c2ccccc2N2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1

Procedure:
One and one-half grams (3.7 m mol) of ethyl 4-[(α-cyano-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate in 15 ml of dioxane were stirred together with 3.7 ml of 1N sodium hydroxide solution for 45 minutes in a bath at 60° C. and for a further 45 minutes in a bath at 80° C. After cooling with ice, the mixture was combined with 3.7 ml of 1N hydrochloric acid, the dioxane was evaporated off in vacuo, and the residue was distributed between water and chloroform. The organic solution was extracted with a small amount of water, dried, filtered, and concentrated by evaporation in vacuo. The evaporation residue was purified by column chromatography on silica gel [chloroform/ethanol (5:1)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:12].N([O-])=[O:15].[Na+].O>Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([OH:15])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1c(Cl)cc(N)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(Cl)cc(O)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
4-Amino-2,6-dichlorobenzoic acid methyl ester (0.5 g) was suspended in 20% HCl (25 mL) and stirred for 30 min then cooled to 0-5° C. After slow addition of NaNO2 (188 mg), the mixture was stirred for 30 min at that temperature and added to boiling water (50 mL). The mixture was then refluxed for 2 h, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2) to give 2,6-dichloro-4-hydroxybenzoic acid methyl ester (275 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]2[C:9]([O:10][CH2:11][CH2:12][N:13]2[S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][CH3:27])(=[O:18])=[O:17])=[N:8][CH:7]=1)=[O:5])C.[OH-].[K+:29]>O1CCCC1>[K+:29].[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([O:26][CH3:27])=[C:19]([S:16]([N:13]2[C:14]3[C:9](=[N:8][CH:7]=[C:6]([C:4]([O-:5])=[O:3])[CH:15]=3)[O:10][CH2:11][CH2:12]2)(=[O:17])=[O:18])[CH:24]=1
Reactant: CCOC(=O)c1cnc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ncc(C(=O)[O-])cc21
Temperature: 50 °C
Reaction time: 72 h
Yield: 91.4 %

Procedure:
A mixture of 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylic acid ethyl ester (124 mg, 0.30 mmol) in tetrahydrofuran (0.6 mL) and 1 M aq. potassium hydroxide solution (0.60 mL, 0.60 mmol) was stirred at 50° C. over 72 h. Evaporation of volatile material furnished 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-4-oxa-1,5-diaza-naphthalene-7-carboxylic acid potassium salt (116 mg), which was directly used in the next step. Light yellow solid, MS (ISP)=383.1 (M−K)−.
Reaction SMILES: [O:1]1[CH2:5]CC[CH2:2]1.[H-].[Na+].[CH3:8][C:9]1[CH:14]=[C:13]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=[C:11]([CH3:22])[C:10]=1[OH:23].COCCl>O>[C:16]([O:15][C:13]1[CH:12]=[C:11]([CH3:22])[C:10]([O:23][CH2:2][O:1][CH3:5])=[C:9]([CH3:8])[CH:14]=1)(=[O:21])[C:17]([CH3:19])([CH3:20])[CH3:18]
Reactant: Cc1cc(OC(=O)C(C)(C)C)cc(C)c1O
Reactant: C1CCOC1
Agent: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCOc1c(C)cc(OC(=O)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50 ml of an anhydrous tetrahydrofuran suspension containing 1.72 g of sodium hydride (55% by weight), 6.75 g of 2,6-dimethyl-4-pivaloyloxyphenol were added in small portions, followed by stirring at room temperature for 30 minutes. To the reaction mixture, 3.18 g of chloromethyl methyl ether were added and the resulting mixture was stirred at the same temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure, whereby 8.17 g of 4-methoxymethoxy-3,5-dimethylphenyl pivaloate were obtained as a crude product.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([S:12][CH3:13])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH2:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN1C(=O)CCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:13][S:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=2[N:8]=1
Reactant: CSc1ncc2ccnc(Cl)c2n1
Reactant: CC(C)(C)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSc1ncc2ccnc(NCC(C)(C)C)c2n1
Temperature: 80 °C
Yield: 73.9 %

Procedure:
To a solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33, 1 g, 4.72 mmol) in NMP (15 mL) was added neopentylamine (5.5 mL, 4.72 mmol). The reaction mixture was heated to 80° C. for 20 hours. The reaction mixture was diluted with saturated aqueous NaHCO3 (50 mL) and EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane give the title compound (915 mg, 74%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:18]>ClCCl.O1CCOCC1>[ClH:18].[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N1CCC(N)CC1

Procedure:
To a solution of O-tert-butyl N-(1-acetylpiperidin-4-yl)carbamate (2.42 g) in dichloromethane (24 ml) was added 4N hydrogen chloride in dioxane (24 ml). The solvents were removed under reduced pressure. After rinse with diisopropyl ether, 1-acetyl-4-aminopiperidine hydrochloride (2.02 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.CCOCC>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)[CH3:6])[CH3:22]
Reactant: CNc1cccc(Cl)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CN(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
To a solution of 3-chloro-N-methylaniline (0.50 g, 3.35 mmol) in ethanol (7 ml) were added sodium carbonate (0.53 g, 5.03 mmol) and ethyl bromoacetate (0.42 ml, 3.69 mmol). The resulting suspension was stirred at room temperature for 1 hour and was then heated at 100° C. for 15 min under microwave irradiation. The mixture was then cooled to room temperature, diluted with ether, and filtered. The filtrate was washed with 1 M aqueous hydrochloric acid, the phases separated, and the aqueous phase extracted with ether. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=gradient 100:0-70:30) to yield a brown oil (0.49 g, 64%); MS (ISP): 230.3, 228.1 ([M+H]+.).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]1[CH:11]=[N:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C@@H:27]2[CH:32]=COC(=O)[O:28]2)[CH:20]=1.O>CN(C)C=O>[O:7]1[CH:11]=[N:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:32][C@H:27]([OH:28])[CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:14][CH:13]=1
Reactant: O=C1OC=C[C@@H](CCc2cccnc2)O1
Reactant: Oc1ccc(-c2nnco2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2nnco2)cc1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
Cesium carbonate (0.72 g) and 4-(1,3,4)-oxadiazol-2-yl-phenol (0.54 g) were added to a solution of (4R)-4-[2-(pyridin-3-yl)ethyl]-1,3-dioxin-2-one (1.20 g, Example 14a)) in dry dimethylformamide (75 ml) and heated at 90° C. for 14 hours. After cooling, the reaction mixture was poured into water (50 ml) and extracted three times with ethyl acetate. The combined organic phases were extracted twice with 2M hydrochloric acid. The combined aqueous extracts were basified by dropwise addition of 2M aqueous sodium hydroxide and the aqueous solution was then extracted three times with ethyl acetate. The organic extracts were combined and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase HPLC eluting with 0 to 25% ethanol in dichloromethane to give the title compound as a solid (0.19 g).