Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:11]3([CH2:20][CH2:19][C:14]4(OCC[O:15]4)[CH2:13][CH2:12]3)[C:10]2=[O:23])=[CH:5][CH:4]=1>O1CCCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:22][CH2:21][C:11]3([CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]3)[C:10]2=[O:23])=[CH:5][CH:4]=1
Reactant: O=C1N(c2ccc(C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)CCN(c1ccc(C(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.5 %

Procedure:
10-(4-Trifluoromethyl-phenyl)-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (6.7 g) was dissolved in tetrahydrofuran (189 ml) aqueous hydrochloric acid solution (2M, 94.3 ml) was added and the mixture was stirred for 12 hours at RT. The reaction mixture was poured into ice/water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to give the title compound as a colorless foam (4.9 g). MS (m/e): 311 [M+].
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:18][Mg]Br.[Cl-].[NH4+].O>O1CCCC1>[N:1]1[C:2]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH3:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1ccc(-c2cn3ccccc3n2)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2cn3ccccc3n2)cc1

Procedure:
Subsequently, 4-imidazo[1,2-a]pyridin-2-ylbenzaldehyde g) was dissolved in tetrahydrofuran (100 mL), followed by stirring under ice cooling. Methyl magnesium bromide (3.0M diethyl ether solution, 4.4 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (5 mL) was added dropwise to the reaction mixture, followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform, followed by drying over magnesium sulfate. The solvent was evaporated, and the solid was recovered through filtration by use of dichloromethane-methanol (30:1) mixture. The filtrate was concentrated under reduced pressure, and the residue was subjected to flash chromatography. Fractions eluted by dichloromethane-methanol (30:1) were concentrated under reduced pressure, and the solid was recovered through filtration by use of diethyl ether. Through the above procedure, 1-(4-imidazo[1,2-a]pyridin-2-ylphenyl)-1-ethanol (2.43 g) was yielded.
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH:13]=O)[C:10]2[N:9]=[C:8]([C:15]#[N:16])[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3]1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[C:15]([C:8]1[N:9]=[C:10]2[C:5]([CH:4]=[CH:3][C:2](=[O:1])[N:11]2[CH2:12][CH2:13][N:39]2[CH2:38][CH2:37][CH:36]([N:28]([CH2:27][C:24]3[N:23]=[CH:22][C:21]4[O:20][CH2:19][CH2:18][O:17][C:26]=4[CH:25]=3)[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:41][CH2:40]2)=[CH:6][CH:7]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: N#Cc1ccc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ccc(C#N)nc32)CC1
Yield: 73 %

Procedure:
A mixture of 7-oxo-8-(2-oxoethyl)-7,8-dihydro-1,8-naphthyridine-2-carbonitrile (329 mg, 1.545 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (539 mg, 1.545 mmol) in chloroform (15 ml) and MeOH (1 ml) was stirred for 2 h before addition of NaBH(OAc)3 (982 mg, 4.635 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the desired compound (620 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH2:14][CH3:15])[CH2:9][C:10](OC)=[O:11])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:18]>O>[Cl:1][C:2]1[C:7]2[C@H:8]([CH2:14][CH3:15])[CH2:9][C:10](=[O:11])[NH:18][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: CCC(CC(=O)OC)c1c(Cl)ncnc1Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC[C@@H]1CC(=O)Nc2ncnc(Cl)c21
Temperature: 200 °C

Procedure:
Dissolve methyl 3-(4,6-dichloropyrimidin-5-yl)pentanoate (10.00 g, 38.01 mmol) in 28% ammonium hydroxide in water (95 mL) and seal in a 350 mL tube. Heat the reaction mixture to 200° C. for 2 hours. Cool the reaction mixture in an ice bath, then filter and wash with cold water. Dry the solids under vacuum to give the racemate. Chiral separation (Chiralpak AS-H, 100% ethanol w/0.2% dimethyl ethylamine) provides the title compound as enantiomer 2 (3.19 g, 40%) (>99% ee). MS (ES) m/z=212 [M]+.
Reaction SMILES: [CH2:1]([P:3]([CH2:6][CH2:7][OH:8])(=[O:5])[OH:4])[CH3:2].[OH-:9].[Na+].C.OO>O.[Pd]>[CH2:1]([P:3]([OH:4])([CH2:6][C:7]([OH:9])=[O:8])=[O:5])[CH3:2]
Reactant: [OH-]
Reactant: CCP(=O)(O)CCO
Agent: [Pd]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CC(=O)O
Temperature: 70 °C
Yield: 92 %

Procedure:
13.8 g (0.1 mol) of ethyl-(2-hydroxyethyl)phosphinic acid (produced as in Example 9) are dissolved in 150 ml of water and adjusted to pH 9 with 2N NaOH solution. Then, 0.25 g of charcoal with 5% Pd and 1% Bi is added, the suspension is heated to 70° C. and 30% strength hydrogen peroxide solution is passed into the suspension at a flow rate of 1 mol equivalent per hour. All the while, the pH of the suspension is maintained at pH=9 by adding 2N NaOH solution. After the reaction has ended, the reaction solution is filtered to remove the catalyst, which is washed, and the filtrate is made acidic with hydrochloric acid and the water is distilled off in vacuo. The residue is taken up in tetrahydrofuran and extracted. The insoluble salts are filtered off to leave 14.0 g (92% of theory) of 2-(ethylhydroxyphosphinyl)acetic acid as a colorless solid material.
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]([C:9]([OH:11])=O)=[N:2]1.CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[NH2:40][C@H:41]([CH2:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=2)=[CH:53][CH:52]=1)[CH2:42][C@:43]([CH2:48][OH:49])([CH3:47])[C:44]([OH:46])=[O:45]>CN(C=O)C>[C:44]([C@:43]([CH3:47])([CH2:48][OH:49])[CH2:42][C@H:41]([NH:40][C:9]([C:3]1[NH:2][N:1]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=1)=[O:11])[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[CH:58]=2)=[CH:53][CH:52]=1)([OH:46])=[O:45]
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(F)c2)cc1)C(=O)O
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2cccc(F)c2)cc1)NC(=O)c1cc(C(=O)O)n[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.2 %

Procedure:
3,5-Pyrazoledicarboxylic acid (37.7 mg, 241 μmol, 1.0 eq.), EDCI (42.7 μL, 241 μmol, 1.0 eq.), 4-methylmorpholine (53.1 μL, 2.0 eq.) and 1 HOBt (32.6 mg, 241 μmol, 1.0 eq.) were combined in DMF (0.2 mL) and stirred for 5 minutes at room temperature. A predissolved solution of (2S,4R)-4-amino-5-(3′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (80 mg, 240 μmol, 1.0 eq.) and 4-methylmorpholine (53.1 μL) in DMF (0.3 mL) was added and the resulting mixture was stirred for 15 minutes. The reaction was quenched by adding AcOH and the product was purified by preparative HPLC and lyophilized to yield the title compound (25 mg). MS m/z [M+H]+ calc'd for C24H24FN3O6, 470.17. found 470.4.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][C@@H:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:18])=[O:3])[O:10]1
Reactant: CCOC(=O)C[C@@H]1OB(O)c2cc(O)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (3S)-(1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.04 g, 4.16 mmol) in THF (5 mL) was treated with lithium hydroxide (0.478 g, 2.08 mmol) in water (5 mL) at 0° C. The solution was stirred at 0° C. for 1 hour then quenched with 2N HCl to pH 2 and concentrated to approximately half of the entire volume. The precipitated solid was collected by vacuum filtration, then rinsed with cold water and dried to give (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid. The filtrate was neutralized with NaHCO3 and lyophilized. The residue was suspended in water (5-10 mL) and stirred for 10 minutes. The solid was collected by vacuum filtration to give a second portion of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as a yellow solid (total product; 0.49 g, 53%). 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.30 (s, 1H), 9.08 (s, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 5.38 (d, J=9.38 Hz, 1H), 3.00 (d, J=15.24 Hz, 1H), 2.20 (s, 3H), 2.00 (dd, J=15.24, 10.16 Hz, 1H). MS (ESI) m/z: 221 [M−1].
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:18])[C:11]([Cl:17])=[C:12]([OH:16])[CH:13]=2)[C:8]1=[O:19])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].Cl>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:18])[C:11]([Cl:17])=[C:12]([O:16][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:13]=2)[C:8]1=[O:19])(=[O:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(=O)OCCC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)C2
Temperature: 60 °C
Yield: 96.3 %

Procedure:
2-(Acetoxyethyl)-6,7-dichloro-2,3-dihydro-5-hydroxy-1H-inden-1-one (5.8 gm, 0.0191 mole), potassium carbonate (3.97 gm, 0.0287 mole), methyl bromoacetate (3.52 gm, 0.023 mole) in dry N,N-dimethylformamide (35 ml) were stirred and heated at 60° C. for 3 hours. The mixture was cooled and poured into a mixture of water and ice containing hydrochloric acid. The resulting mixture was extracted with a mixture of ether and tetrahydrofuran then methylene chloride. The combined organic extracts were washed with water, then with brine and finally dried over MgSO4. Evaporation of the solvent gave 6.9 gm of residue which was purified by column chromatography using silica (300 gm) and eluting with a 50/1 mixture of methylene chloride and tetrahydrofuran. Combining the appropriate fractions and evaporating the solvent gave 3.3 gm of product, m.p. 111°-113° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH3:23])[CH2:20][CH2:21][CH3:22])[CH:3]=1.[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40](O)=[O:41])[CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:30].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40]([O:1][C:2]2[C:11]3[CH:10]4[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]4[C:8]([CH3:18])([CH3:17])[O:7][C:6]=3[CH:5]=[C:4]([C:19]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([CH3:23])[CH2:20][CH2:21][CH3:22])[CH:3]=2)=[O:41])[CH2:33][CH2:32]1
Reactant: CCCC(C)(c1ccccc1)c1cc(O)c2c(c1)OC(C)(C)C1CCC(C)=CC21
Reactant: O=C(O)CCCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccccc1)c1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1CCC(C)=CC21

Procedure:
0.7 g. (2.33 mmoles) of 1-Hydroxy-3-(phenyl- 1-methylbutyl)-6,6,9-trimethyl-6a,7,8,10a-tetrahydrodibenzo [b,d]pyran, prepared according to the method of Example 48, 0.48 g. (2.28 mmoles) of γ-morpholinobutyric acid hydrochloride (Cruichshank and Sheehan, J. Am. Chem. Soc. 83, 2891 (1961), m.p. 180°-182° ) and 0.48 g. (2.35 mmoles) of dicyclohexylcarbodiimide (Aldrich) are combined with 35 ml. of methylene chloride and stirred at room temperature for a total of 40 hours. The insoluble by-product of dicyclohexylurea is removed using a rotary evaporator. The resulting residue is dissolved in about 20 ml. of benzene and a small amount of insoluble material is removed by filtration. The benzene is evaporated and the residue dried in vacuo to give 0.7 g. of material. Crystallization from benzene/pet ether yields the crystalline product.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([O:32][CH3:33])[C:26]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)=[C:25]3[Cl:45])([C:14]2[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[OH:13])[CH2:9]1)=O)(C)(C)C.C(O)=O.Cl>CO>[NH:8]1[CH2:11][CH:10]([C:12]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([O:32][CH3:33])[C:26]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=2)=[C:25]3[Cl:45])([C:14]2[C:15]([CH3:21])=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[OH:13])[CH2:9]1
Reactant: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CNC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.75 h

Procedure:
To a flask containing tert-butyl 3-((4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidine-1-carboxylate (700 mg, 1.09 mmol, Example 125) was added formic acid (10 mL, 265 mmol) at room temperature followed by 6 N aqueous HCl (500 μL). After 45 minutes, MeOH was added (10 mL) and the mixture was stirred for 15 minutes and then concentrated to provide the title compound as a crude product. MS (ESI): mass calcd. Chemical Formula: C29H27ClF3N3O2; Exact Mass: 541.2. m/z found 541.9 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:11])[CH2:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH3:3].[CH:12]([O-])([O-])[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[CH2:14]([O:13][CH:12]=[C:5]([C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[C:4](=[O:11])[CH:2]([CH3:1])[CH3:3])[CH3:15]
Reactant: CCOC([O-])[O-]
Reactant: CC(C)C(=O)CC(=O)C(C)C
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)C(C)C)C(=O)C(C)C
Yield: 49.2 %

Procedure:
A mixture comprising 17.2 g (110 mmol) of 2,6-dimethyl-3,5-heptanedione, 22.8 g (153 mmol) of ethyl orthoformate and 31.5 g (309 mmol) of acetic anhydride, was reacted for 2 hours at 110° C. The solvent was distilled off under reduced pressure to obtain 11.5 g (yield: 49%) of 4-ethoxymethylene-2,6-dimethyl-3,5-heptanedione.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:7]1[CH:8]=[C:9]2[CH2:23][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=3[C:14](=[O:15])[C:10]2=[C:11]([OH:13])[CH:12]=1>C1C=CC=CC=1.N1C=CC=CC=1>[OH:22][C:21]1[C:16]2[C:14](=[O:15])[C:10]3[C:9](=[CH:8][CH:7]=[CH:12][C:11]=3[OH:13])[CH:23]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: CCCC(=O)Cl
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCC(=O)C1c2cccc(O)c2C(=O)c2c(O)cccc21

Procedure:
28.6 g (0.27 moles) butyryl chloride is added, while stirring, to a mixture containing 50.9 g (0.225 moles) anthraline in 1575 ml benzene and 27.5 ml pyridine. The reaction mixture is cooked using a return condenser for 10 hours while stirring. The solution is filtered and the filrate is evaporated dry under a lowered pressure. The residue is crystallized out from acetic acid. Yield 17.0 g (25.5% of the theoretical).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:12][P:13]([NH:18][CH2:19][CH3:20])([NH:15][CH2:16][CH3:17])=[S:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O>C(O)C>[CH2:16]([NH:15][P:13]([CH2:12][NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([NH:18][CH2:19][CH3:20])=[S:14])[CH3:17]
Reactant: CCNP(=S)(CN(CC(=O)OCC)C(=O)C(F)(F)F)NCC
Solvent: CCO
Product: CCNP(=S)(CNCC(=O)OCC)NCC
Yield: 20.4 %

Procedure:
N-trifluoroacetyl-N-[bis(ethylamino)phosphinothioylmethyl]glycine, ethyl ester (2 g, 0.0055 mole), was dissolved in ethanol. The solution was stirred and sodium tetrahydrido boron (210 mg, 0.0055 mole) was added portionwise over a ten minute period. The solution was stirred for an additional 40 minutes. The solvent was removed by evaporation under vacuum and the residue was washed with water. The water washings were saturated with sodium chloride and the aqueous layer and insoluble residue were simultaneously extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was then chromatographed on silica gel employing dichloromethane and then ether to yield N-[bis(ethylamino)phosphinothioylmethyl]glycine, ethyl ester (300 mg), ND25 =1.5128 and having the following analysis: Calculated: C, 40.44; H, 8.30; N, 15.72; P, 11.59; S, 11.99. Found: C, 40.19; H, 8.06; N, 15.37; P, 11.33; S, 11.74.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=2)[NH:9]1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1>N1C=CC=CC=1.O>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:29])[CH2:17][C:16]2([CH3:18])[CH3:19])#[N:21]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(C#N)cc21
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-aminophenyl)-4,4-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (500 mg, 1.8 mmol) in pyridine (3 mL) was added pyridine-3-sulfonyl chloride (385 mg) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Sodium sulfate, and then concentrated. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide LC/MS m/e obsd. (ESI+) [(M+H)+] 419.3.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.[Pd]>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:17]1[CH2:16][CH2:15][N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:19][CH2:18]1
Reactant: COc1ccccc1N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1N1CCN(C2CCNCC2)CC1
Yield: 95.6 %

Procedure:
A solution of 4-(1-benzylpiperidine-4-yl)-1-(2-methoxyphenyl)piperazine (Step 1, 20.0 g) in ethanol (120 mL) containing acetic acid (12 mL) was hydrogenated over 10% palladium on carbon (1 g) at 50 psig on a Parr apparatus for 12 hours. The catalyst was removed by filtration through Celite and the mixture was concentrated to dryness on a rotary evaporator. The residue was partitioned between chloroform and saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated on a rotary evaporator to provide the desired product (14.4 g) as a yellow oil which was used without further purification. The compound was characterized as the dihydrochloride salt, which was formed by dissolving the oil in ethanol and treating it with an excess of 1N HCl/Et2O to give an off-white precipitate, which was collected by vacuum filtration, washed with Et2O and dried in vacuo; MP. 274-288° C.; MS (ES) m/z (relative intensity): 276 (M+H)+ (100).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>[Pd].CCO>[CH3:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH:3]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)c2cccnc2n1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C(C)c2cccnc2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
In a 100 mL round-bottomed flask, 1-tert-butyl 2-ethyl 3-methyl-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (235 mg, 772 μmol, Eq: 1.00) was combined with EtOH (34 mL) to give a colorless solution. 10% Palladium on carbon (82.2 mg, 77.2 μmol, Eq: 0.1) was added and the reaction was stirred under a hydrogen atmosphere (balloon) at rt overnight. The reaction mixture was filtered through Celite and concentrated in vacuo to give 1-tert-butyl 2-ethyl 3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (235 mg), m/z=307 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][C@@H:24]3[O:26][CH2:25]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][C@H:24]([OH:26])[CH2:25][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OC[C@H]4CO4)cc(OC4CCOCC4)c23)c1
Reactant: C1COCCN1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OC[C@H](O)CN4CCOCC4)cc(OC4CCOCC4)c23)c1
Temperature: 45 °C

Procedure:
A mixture of 4-(2-chloro-5-methoxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.08 g), morpholine (0.044 ml), ethanol (1 ml) and chloroform (1 ml) was stirred and heated to 45° C. for 16 hours. The mixture was cooled to ambient temperature and evaporated. The residue was triturated under pentane. The resultant solid was isolated, washed with diethyl ether and dried under vacuum to give the title compound (0.08 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 1.9–2.05 (m, 2H), 2.15 (d, 2H), 3.1–3.45 (m, 5H), 3.45–3.6 (m, 3H), 3.7–3.9 (m, 2H), 3.8 (s, 3H), 3.9–4.1 (m, 2H), 4.22 m, 1H), 4.45 (m, 1H), 5.15 (m, 1H), 6.95 (s, 1H), 7.02 (m, 1H), 7.15 (s, 1H), 7.5–7.6 (m, 2H), 8.9 (s, 1H); Mass Spectrum: M+H+ 545 and 547.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)C1)=O)(C)(C)C.[CH3:33][C@H:34]1CN[CH2:37][C@@H:36](C)[NH:35]1>>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:24]2[N:25]=[C:17]([CH2:16][N:12]3[CH2:13][C@H:36]([CH3:37])[NH:35][C@H:34]([CH3:33])[CH2:11]3)[S:18][C:19]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Reactant: C[C@@H]1CNC[C@H](C)N1
Product: C[C@@H]1CN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)C[C@H](C)N1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using cis-2,6-dimethyl-piperazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a pale yellow solid (32 mg, 42%).