Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=C=NC(C)C)(C)C.[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O.ON1C2C=CC=CC=2N=N1.[OH:50][CH2:51][C@@H:52]([C@@H:54]([C@@H:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[OH:57])[OH:55])[NH2:53]>O1CCCC1>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([NH:53][C@H:52]([C@@H:54]([C@@H:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[OH:57])[OH:55])[CH2:51][OH:50])=[O:39]
Reactant: O=C(O)CCCCCCCCCCCCCCCCCCCCCCCCCCO
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@H](CO)NC(=O)CCCCCCCCCCCCCCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylcarbodiimide (1 ml, 6.4 mmoles) was added to a stirred suspension of 27-hydroxy-heptacosanoic acid (2.13 g, 5 mmoles), dry tetrahydrofuran (50 ml), dried 1-hydroxy-benzotriazole (1.6 g, 13.5 mmoles) and phytosphingosine (1.5 g, 4.7 mmoles) at 40° C. under nitrogen. After stirring overnight the mixture was cooled to room temperature and the precipitate was filtered off and washed with 20 ml of tetrahydrofuran.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:21]([N:24]([CH:26]1[CH:30]([CH3:31])[CH2:29][NH:28][CH2:27]1)[CH3:25])(=[O:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([N:24]([CH:26]1[CH:30]([CH3:31])[CH2:29][N:28]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:27]1)[CH3:25])(=[O:23])[CH3:22]
Reactant: CC(=O)N(C)C1CNCC1C
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N(C)C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-(N-acetyl-N-methylamino)-4-methylpyrrolidine (0.42 g) and DBU (0.27 g) was refluxed for an hour and allowed to stand overnight. The resulting precipitate was collected by filtration and washed with acetonitrile-ether to give the title compound (0.56 g) as pale yellow powder.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C([O:13][C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)O)(=O)O.C(=O)=O>>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]1([CH3:5])[O:13][C:14]2[CH:15]=[CH:17][CH:18]=[CH:19][C:20]=2[O:4]1)[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(O)Oc1ccccc1O
Agent: O=C=O
Product: CCOC(=O)CC1(C)Oc2ccccc2O1

Procedure:
13 g of ethyl acetoacetate and 13.6 g of pyrocatechol carbonate are heated until evolution of CO2 ceases. The residue is distilled under reduced pressure, b.p. 83°-86°C/0.3 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29]N)[C:24]=2[F:31])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]3[C:6]4[CH2:5][C:4]5[C:8](=[CH:9][CH:10]=[C:2]([NH2:1])[CH:3]=5)[C:7]=4[NH:29][C:25]=3[C:24]=2[F:31])=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(N)cc2C4)cc1
Yield: 17 %

Procedure:
The title material is prepared in 17% yield by reacting 5-Amino-indan-1-one (commercially available) and (4′-Butyl-2-fluoro-biphenyl-3-yl)-hydrazine hydrochloride (Example 78, step) in an analogous manner to example 1, step 3; LC/MS calculated for [M+H]+ C25H23FN2: 371.2, found: 371.2.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[ClH:1].[ClH:1].[NH2:23]/[C:22](=[N:25]\[OH:26])/[C:20]1[CH:19]=[CH:18][C:16]2[CH:17]=[C:13]([C:11]([NH:10][C@@H:4]3[CH:5]4[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]4)[CH2:3]3)=[O:12])[S:14][C:15]=2[CH:21]=1
Reactant: N#Cc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N/C(=N\O)c1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Temperature: 80 °C

Procedure:
800 mg (2.0 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-cyano-1-benzo-thiophene-2-carboxamide hydrochloride, 278.1 mg (4.0 mmol) of hydroxylamine hydrochloride and 829.5 mg (6.0 mmol) of potassium carbonate in 8 ml of an 8:1 mixture of water and ethanol are heated at 80° C. for 3 h. The mixture is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol/25% ammonia 100:20:4). The product fractions are combined and concentrated, methanol and 4M HCl in dioxane are added and the mixture is then again concentrated and dried under high vacuum. 447.3 mg (53.6% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[H-].[Na+].Cl[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1>CN(C)C=O>[CH3:18][C:17]1[C:12]([O:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=1
Reactant: OCc1ccccn1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1OCc1ccccn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
2-Pyridylcarbinol (1.96 g, 18 mmol) in dry dimethylformamide (20 ml) was cooled to −20° C. and treated with sodium hydride (0.48 g of 80% dispersion in mineral oil, 16 mmol). The mixture was stirred under argon at −20° C. for one hour then a solution of 2-chloro-3-methyl-5-nitropyridine (2.07 g, 12 mmol) in dry dimethylformamide (10 ml) was added and the mixture was allowed to warn to room temperature over 16 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (3×100 ml) and 10% aqueous sodium hydroxide solution(75 ml). The combined organics were dried (Na2SO4) and evaporated in vacuo to a residue which was subjected to flash column chromatography with 1:1 ethyl acetate/petroleum ether as eluant to afford the title compound (1.47 g, 51%) as lemon yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][C:16]([O:18][CH:19]([C:23]([O:25]C)=O)[C:20]([CH3:22])=[CH2:21])=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.S1(=O)C2C=CC=CC=2N=C1.O>C1(C)C=CC=CC=1.C[O-].[Na+]>[F:1][C:2]1[C:14]([N:15]2[C:23](=[O:25])[C:19](=[C:20]([CH3:22])[CH3:21])[O:18][C:16]2=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: C#CCn1c(=O)sc2cc(F)c(NC(=O)OC(C(=C)C)C(=O)OC)cc21
Agent: C[O-]
Agent: O=S1C=Nc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCn1c(=O)sc2cc(F)c(N3C(=O)OC(=C(C)C)C3=O)cc21
Temperature: 25 °C

Procedure:
To a solution of 6-fluoro-5-(1-methoxycarbonyl-2-methyl-2-propenyloxycarbonylamino)-3-propargyl-2(3H)-benzothiazolone (10 g) in toluene (100 g), sodium methylate was added in an amount of 0.05 equivalent to one equivalent of the benzothiazolone. The resulting mixture was refluxed for 3 hours, cooled to room temperature, combined with water and extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography to give Compound No. 40 (6.8 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:18]([OH:20])=O)[NH:13]3)[N:6]=1.[NH2:21][CH:22]1[CH2:27][CH2:26][C:25]([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([CH3:38])[CH2:32]2)([OH:28])[CH2:24][CH2:23]1>>[OH:28][C:25]1([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][C@H:34]([OH:37])[C@@H:33]([CH3:38])[CH2:32]2)[CH2:26][CH2:27][CH:22]([NH:21][C:18]([C:12]2[NH:13][C:14]3[C:10]([CH:11]=2)=[C:9]([O:8][CH2:7][C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)[CH:17]=[CH:16][CH:15]=3)=[O:20])[CH2:23][CH2:24]1
Reactant: O=C(O)c1cc2c(OCc3csc(Cl)n3)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5csc(Cl)n5)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(2-chloro-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid 16d and amine 14.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:34][O:33][CH2:32]5)[CH2:27][C@@H:26]4[CH2:35][CH3:36])=[CH:21][N:20]=3)[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=2)=[CH:10][C:9]([F:39])=[CH:8][C:7]=1[N:40]1[CH2:51][CH2:50][N:49]2[C:42](=[CH:43][C:44]3[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=32)[C:41]1=[O:54])(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[CH2:35]([C@H:26]1[CH2:27][N:28]([CH:31]2[CH2:32][O:33][CH2:34]2)[CH2:29][CH2:30][N:25]1[C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:37])[N:14]([CH3:38])[CH:13]=[C:12]([C:11]3[C:6]([CH2:5][OH:4])=[C:7]([N:40]4[CH2:51][CH2:50][N:49]5[C:48]6[CH2:47][C:46]([CH3:53])([CH3:52])[CH2:45][C:44]=6[CH:43]=[C:42]5[C:41]4=[O:54])[CH:8]=[C:9]([F:39])[CH:10]=3)[CH:17]=2)=[N:20][CH:21]=1)[CH3:36]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A mixture of 114g (115 mg, 0.16 mmol) and lithium hydroxide (38 mg, 1.6 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduced pressure and the residue was extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 114 (45 mg, 40%) as a white solid. MS: [M+H]+ 696.4. 1H NMR (500 MHz, CDCl3) δ 8.55-8.54 (m, 1H), 7.91 (s, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.47 (s, 1H), 7.26 (d, J=3.0 Hz, 1H), 7.17 (d, J=9.0 Hz, 1H), 6.95 (dd, J=2.5, 8.5 Hz, 1H), 6.83-6.81 (m, 2H), 4.71 (t, J=6.5 Hz, 2H), 4.67 (t, J=6.0 Hz, 1H), 4.62 (t, J=6.0 Hz, 1H), 4.57-4.55 (m, 1H), 4.41-4.38 (m, 1H), 4.32-4.30 (m, 1H), 4.24-4.14 (m, 3H), 3.92-3.87 (m, 1H), 3.71 (s, 3H), 3.56-3.50 (m, 1H), 3.33-3.29 (m, 1H), 3.13-3.11 (m, 2H), 2.58-2.56 (m, 3H), 2.52 (s, 2H), 2.44-2.43 (m, 2H), 2.38-2.32 (m, 1H), 1.66-1.64 (m, 1H), 1.42-1.37 (m, 1H), 1.28 (s, 6H), 0.82 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:19]4[CH2:21][NH:22][CH2:23][CH2:24][C:18]=4[NH:17][C:16]=3[N:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:25](OC(=O)C)(=[O:27])[CH3:26].CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O.O>[C:25]([N:22]1[CH2:23][CH2:24][C:18]2[NH:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:11][CH:10]=4)[C:20]=3[C:19]=2[CH2:21]1)(=[O:27])[CH3:26]
Reactant: CNS(=O)(=O)c1ccc(-c2ccnc3[nH]c4c(c23)CNCC4)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(-c2ccnc3[nH]c4c(c23)CN(C(C)=O)CC4)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
N-Methyl-4-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-benzenesulfonamide (75 mg, 0.22 mmol), acetic anhydride (22 mg, 0.22 mmol), and DIEA (0.07 mL, 0.44 mmol) were dissolved in dioxane (2.0 mL), and stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc/H2O. The resulting precipitate was filtered, washed with EtOAc, and dried under vacuum to provide 14 (40 mg, 48% yield) as a tan solid. LC-MS (M+H=385, obsd.=385).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][NH:12][CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9].[OH-].[Na+].Br[CH2:19][CH3:20]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]23[CH2:15][CH:14]2[CH2:13][N:12]([CH2:19][CH3:20])[CH2:11]3)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CCBr
Reactant: Clc1ccc(C23CNCC2C3)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN1CC2CC2(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 4 h
Yield: 66.4 %

Procedure:
A stirred solution of 1-(3,4-dichlorophenyl)-3-aza-bicyclo[3.1.0]hexane hydrochloride (19.3 g, 72.9 mmol) in CH2Cl2 (100 mL) was rendered basic with 2N NaOH (100 mL). The resulting mixture was extracted with CH2Cl2 (2×100 mL) and the combined extracts dried, filtered and concentrated under reduced pressure. The residue was dissolved in acetonitrile (200 mL) and bromoethane (15.9 g, 146 mmol) added at room temperature. The mixture was stirred for 4 h during which time a white precipitate formed. After this time the reaction was concentrated under reduced pressure then treated with 2N NaOH (200 mL). Subsequent extraction with CH2Cl2 (3×100 mL) drying the combined extracts (MgSO4), filtration and concentration under reduced pressure afforded a crude residue. This residue was purified by passing through a silica gel plug, eluting with ether, to yield the title compound (12.4 g, 66%) as a clear, viscous oil. This material was then used directly for either chiral separation or hydrochloride salt formation as provided in Example II, Section D hereinbelow.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:14]=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:23][N:24]1[C:28]([CH3:29])=[C:27]([CH:30]=O)[C:26]([CH3:32])=[N:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([N:17]3[CH2:22][CH2:21][N:20]([CH2:30][C:27]4[C:26]([CH3:32])=[N:25][N:24]([CH3:23])[C:28]=4[CH3:29])[CH2:19][CH2:18]3)=[N:13][CH:14]=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: Cc1nn(C)c(C)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1CN1CCN(c2nccnc2-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.01 h
Yield: 91.5 %

Procedure:
Suspend 3′-(4-methanesulfonylphenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.191 g, 0.60 mmol) in tetrahydrofuran (4 mL). Add 1,3,5-trimethyl-1H-pyrazole-4-carbaldehyde (0.087 g, 0.63 mmol) in tetrahydrofuran (435 μL), then sodium triacetoxyborohydride (0.13 g, 0.63 mmol). Subject reaction to ultrasound for 30 sec. then stir under nitrogen at room temperature for 7 hr. Add saturated aqueous sodium hydrogen carbonate (10 mL) followed by 2 N sodium hydroxide (1 mL) to the mixture and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 0:100 to 12:88 methanol:DCM), to give the title compound (241.9 mg, 91%). MS (ES): m/z=441.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CO.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: NC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(Cl)ccc1C(=O)NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
4-Chloro-2-methylbenzoic acid (2.06 g, 12 mmol) was dissolved in DCM (50 mL) and DMF (10 mL) and the solution was cooled to an ice-water bath. To this solution was added a solution of tetrahydropyran-4-yl amine (1.22 g, 12 mmol, 1.05 equiv.) in 10 mL of DCM, followed by N-methylmorpholine (5.75 g, 8 mL, 75 mmol, 3 equiv.), 1-hydroxylbenzotriazole (HOBT) (4.4 g, 32.5 mmol, 1.3 equiv.), sequentially, and finally EDC.HCl (2.97 g, 15.6 mmol, 1.3 equiv.). The resultant clear light brown solution was stirred at r.t. overnight. TLC (5% MeOH in DCM) and LC/MS detected the product peak at retention time of 2.878 min with MS 284/286. The reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and 10 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (15 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to get 2.09 g (69% yield) of the titled compounds as white solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5](C)([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18]2)=[C:13]([Cl:23])[CH:12]=1)[C:6](OCC)=O)C.[OH-].[K+].O>C(O)CCC>[Cl:23][C:13]1[CH:12]=[C:11]([CH:5]([CH3:6])[C:4]([OH:25])=[O:3])[CH:16]=[CH:15][C:14]=1[N:17]1[CH:21]=[C:20]([Cl:22])[CH:19]=[N:18]1
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(-n2cc(Cl)cn2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Solvent: O
Product: CC(C(=O)O)c1ccc(-n2cc(Cl)cn2)c(Cl)c1

Procedure:
3.83 g (10 mmoles) of methyl-[3-chloro-4-(4-chloropyrazol-1-yl) phenyl] malonic acid diethyl ester, 1.4 g of potassium hydroxide, 5 ml of water and 15 ml of n-butanol are heated to the boil for 3 hours, with stirring. The solvent is evaporated off, the residue is dissolved in water, the aqueous solution is extracted with ether, acidification is effected with hydrochloric acid and the precipitate is filtered off. 2-[3-chloro-4-(4-chloropyrazol-1-yl) phenyl] propionic acid is obtained; m.p. 102°-103° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15]([NH:33][C:34](=[O:37])[CH2:35]Br)=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[C:23]2=[O:32])[CH:18]=1>CC#N>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14]1[C:15]([NH:33][C:34](=[O:37])[CH2:35][N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][N:22]2[C:26](=[O:27])[C:25]3[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=3[C:23]2=[O:32])[CH:18]=1
Reactant: CNCCO
Reactant: O=C(CBr)Nc1cn(CCCN2C(=O)c3ccccc3C2=O)cc1-c1ccc(Cl)cc1Cl
Solvent: CC#N
Product: CN(CCO)CC(=O)Nc1cn(CCCN2C(=O)c3ccccc3C2=O)cc1-c1ccc(Cl)cc1Cl
Reaction time: 12 h
Yield: 21 %

Procedure:
N-Methyl ethanolamine (2 eq) was added to a stirred solution of N-{4-(2,4-dichlorophenyl)-1-[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]pyrrol-3-yl}-2-bromcacetamide (6) (8.65 eq) in CH3CN at RT. The reaction was monitored by LC/MS and was determined to be complete after 12 hours. The reaction was concentrated and purified by silica column chromatography eluting with MeOH in CH2Cl2 (5:95, v/v). After collecting the purified fractions and concentrating, N-{4-(2,4-dichlorophenyl)-1-[3-(1,3-dioxobenzo[c]azolin-2-yl)propyl]pyrrol-3-yl}-2-[(2-hydroxyethyl)methylamino]acetamide (7) was obtained as a light yellow glass (21% yield, LC/MS m/z 530.4 MH+) in 95% purity.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:12][P:13]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[S:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O>C(O)C>[N:15]1([P:13]([CH2:12][NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[S:14])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)CN(CP(=S)(N1CCCC1)N1CCCC1)C(=O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)CNCP(=S)(N1CCCC1)N1CCCC1
Yield: 26.5 %

Procedure:
N-trifluoroacetyl-N-[bis(pyrrolidino)phosphinothioylmethyl]glycine, ethyl ester (2.7 g, 0.00649 mole), was dissolved in ethanol. The solution was stirred and sodium tetrahydrido boron (245 mg, 6.49 mm) was added portionwise over a ten minute period. The solution was stirred for an additional 20 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 ether as an eluant to yield N-[bis(pyrrolidino)phosphinothioylmethyl]glycine, ethyl ester (550 mg), ND25 =1.530 and having the following analysis: Calculated: C, 48.88; H, 8.21; N, 13.16. Found: C, 48.65; H, 8.12; N, 13.04.
Reaction SMILES: [NH2:1][C:2]([CH:8]1[CH2:10][CH2:9]1)([CH:5]1[CH2:7][CH2:6]1)[C:3]#[N:4].[H-].C([Al+]CC(C)C)C(C)C>>[CH:5]1([C:2]([CH:8]2[CH2:10][CH2:9]2)([NH2:1])[CH2:3][NH2:4])[CH2:7][CH2:6]1
Reactant: N#CC(N)(C1CC1)C1CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: NCC(N)(C1CC1)C1CC1

Procedure:
This material was obtained according to example 65, step A] α-amino-α-cyclopropyl-cyclopropaneacetonitrile (266 mg) by reduction with diisobutylaluminiumhydride (20% in toluene, 8.1 mL) as a colorless semisolid (106 mg) after purification by flash chromatography (ethyl acetate/MeOH/NH4OH 1:1:0.1). 1H-NMR (CDCl3): 2.66 (s, 2H); 1.70 (s, br, >4H, 4 NH and H2O), 0.71 (m, 2H), 0.40-0.21 (m, 8H).
Reaction SMILES: [NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2OCC[O:20]2)[CH:14]=1.Cl>C(O)C>[NH2:1][C:2]1[C:5](=[O:6])[C:4](=[O:7])[C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=1
Reactant: Nc1c(NCCCOc2cccc(C3OCCO3)c2)c(=O)c1=O
Agent: Cl
Solvent: CCO
Product: Nc1c(NCCCOc2cccc(C=O)c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
The 1-amino-2-{3-[3-(1,3-dioxolan-2-yl)phenoxy]propylamino}-1-cyclobutene-3,4-dione (11.66 g, 0.037 mole) was suspended in a solution of 200 mL of 95% ethanol and 20 mL of aqueous 2.0N HCl. The suspension was stirred at ambient temperature for 2 hours, then filtered (slowly) and dried in vacuo to give 9.85 g of crude title compound. Recrystallization from 150 mL of 95% ethanol and 35 mL of aqueous 1N HCl yielded 5.74 g of purified title compound; mp=203°-206° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]([C:11]([O:13]C)=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1.O[Li].O>C1COCC1.CO.O>[CH3:1][C:2]1[S:3][C:4]2[CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: COC(=O)C1CCCc2nc(C)sc21
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(s1)C(C(=O)O)CCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-7-carboxylate (59 mg, 0.28 mmol) and LiOH.H2O (14 mg, 0.33 mmol) in THF/MeOH/H2O (2.5 mL, 3:1:1) was stirred at RT for 2 h. The mixture was acidified to pH=3 and extracted with EtOAc. The comb. org. layers were dried over MgSO4, and conc. in vacuo.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[O:12])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[CH2:13]=[O:14].Cl.[Cl-].[NH4+]>[OH-].[K+].CO>[OH:14][CH2:13][C:2]1([CH3:1])[C:11](=[O:12])[CH2:10][CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3]1
Reactant: CC1CC2(CCC1=O)OCCO2
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC1(CO)CC2(CCC1=O)OCCO2
Reaction time: 0.5 h
Yield: 56 %

Procedure:
7-Methyl-1,4-dioxaspiro[4.5]decan-8-one (10.5 g, 62 mmol) was dissolved in methanolic potassium hydroxide solution (10 w/w %, 60 g). To the solution was added dropwise a solution of aqueous formaldehyde solution (37%, 4.6 ml) in methanol (5 ml) under ice-cooling over 20 min, and the mixture was stirred for 30 min. Then, to the reaction mixture were added 1 N hydrochloric acid and saturated aqueous ammonium chloride solution, and the mixture was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (6.9 g, yield 56%).