Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21][N:20]([C:22]([O:24][C@H:25]5[CH2:29][CH2:28][O:27][CH2:26]5)=[O:23])[CH2:19]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.C[O-].[Na+].CO>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][N:20]([C:22]([O:24][C@H:25]5[CH2:29][CH2:28][O:27][CH2:26]5)=[O:23])[CH2:21]4)[C:14]([F:30])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CN(C(=O)O[C@H]5CCOC5)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O[C@H]1CCOC1)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 60 °C
Yield: 55 %

Procedure:
(S)-tetrahydrofuran-3-yl 3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)azetidine-1-carboxylate, 6d, was dissolved in methanol (2 mL) and then treated with of 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube. LCMS showed complete reaction after 10 minutes. The resulting solution was quenched with aqueous saturated NH4Cl solution (0.5 mL) then evaporated to dryness and the residue dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 25.9 mg (55% yield) of the desired product, 422, as a solid.
Reaction SMILES: C(N(CC)C/C=C\C1C=C(F)C=CC=1S(CC1C(C(OC)=O)=C(OC)C([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=CC=1)(=O)=O)C.[C:37]1([S:43]([CH2:46][C:47]2[C:52]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[C:51]([O:58][CH3:59])[C:50](I)=[C:49]([O:61][CH3:62])[CH:48]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[C:37]1([S:43]([CH2:46][C:47]2[C:52]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[C:51]([O:58][CH3:59])[C:50]([C:30]3[CH:34]=[CH:33][O:32][CH:31]=3)=[C:49]([O:61][CH3:62])[CH:48]=2)(=[O:45])=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)cc(OC)c(I)c1OC
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)cc(OC)c(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 160, starting from ethyl 6-(benzenesulphonylmethyl)-3-iodo-2,4-dimethoxybenzoate (Intermediate 201), using THF instead of dioxane.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:21][N:22]=3)[N:19]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:24][CH2:23][C:20]1[N:18]2[N:19]=[C:14]([C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH2:12][CH2:11][CH2:10][C:9]4=[O:13])=[C:2]([F:1])[CH:3]=3)[CH:15]=[CH:16][C:17]2=[N:22][N:21]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50 mL recovery flask was charged with tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.117 g, 0.274 mmol), TFA (0.0211 ml, 0.274 mmol), and DCM (0.0177 ml, 0.274 mmol), then stirred open to air at room temperature for 2 hours. The mixture was concentrated, then taken up in MeOH. K2CO3 was added, and this was stirred for 1 hour. The mixture was concentrated, then the residue was taken up in MeOH/CHCl3 then filtered. The filtrate was evaporated, taken up in water, then passed through a reverse phase C18 column, eluting with MeOH/DCM, then concentrated.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:15]=[N+:16]([O-:39])[CH:17]=[C:18]([Cl:38])[C:19]=1[CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[OH:22].[O:40]=[C:41]1[C:50](=[O:51])[NH:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]1[CH2:52][C:53](O)=[O:54]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[N+:16]([O-:39])[CH:17]=[C:18]([Cl:38])[C:19]=1[CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([F:32])[F:31])=[C:25]([O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)[CH:24]=1)[O:22][C:53](=[O:54])[CH2:52][N:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[NH:49][C:50](=[O:51])[C:41]1=[O:40]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cn1c(=O)c(=O)[nH]c2ccccc21)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC HCl) (59 mg, 0.309 mmol) was added to a solution of compounds (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (100 mg, 0.238 mmol), 2-(2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)acetic acid (63 mg, 0.286 mmol) and 4-dimethylaminopyridine (6 mg, 0.048 mmol) in CH2Cl2 (1 mL) at room temperature under nitrogen atmosphere. The mixture was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 (5 mL) and washed with NaHCO3 saturated solution (5 mL), HCL 0.1 N (5 mL) and brine (5 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated, to yield 70 mg of the title compound (80% yield). MS/ESI+ 621.09 [MH]+
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.[CH3:6][O:7][C:8]([CH:10]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:9]>ClCCl>[CH3:6][O:7][C:8](=[O:9])[CH:10]=[C:3]1[CH2:2][O:1][CH2:4]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COC1
Solvent: ClCCl
Product: COC(=O)C=C1COC1
Reaction time: 0.25 h
Yield: 64 %

Procedure:
Oxetan-3-one (commercially available) (50 mg, 0.69 mmol) was solved in 1 ml dichloromethane and cooled to 0-5° C. (Methoxycarbonylmethylene) triphenylphosphorane (255 mg, 0.76 mmol) was added and the mixture stirred for 15 minutes. The mixture was directly purified with column chromatography on silica gel using heptane:ethyl acetate 100:0->0:100. The product fractions were concentrated to give 57 mg (64% yield) of a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.O[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[C@H:20]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19][CH2:18]3)=[N:7][CH:8]=1)#[N:11]
Reactant: N#Cc1ccc(OCCCO)nc1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
To a solution of 6-(3-hydroxypropoxy)nicotinonitrile (Example 257) (0.86 g, 4.83 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.89 g, 4.02 mmol) in THF (20 mL) was added triphenylphosphine (1.49 g, 5.63 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (1.44 g, 5.63 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h and concentrated under reduced pressure. The product (1.22 g, 80%) was isolated after purification by silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.47 (dd, 1H), 7.79 (dd, 1H), 7.05 (d, 1H), 6.82 (d, 1H), 6.77 (d, 1H), 6.69 (dd, 1H), 4.56 (t, 2H), 4.16 (q, 2H), 4.11 (t, 2H), 3.51 (qt, 1H), 2.95-2.78 (m, 2H), 2.70 (dd, 1H), 2.44-2.32 (m, 2H), 2.30-2.20 (m, 2H), 1.80-1.70 (m, 1H), 1.28 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N:19]=[C:20]=[O:21])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:22]=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1.FC1C=CC=CC=1[C:32]1C2C=C(NC(NCCO)=O)C=CC=2N2C=NN=C2[CH2:34][N:33]=1.NC1C=CC2N3C=NN=C3CN=C(C3C=CC=CC=3Cl)C=2C=1.C(=O)([O-])[O-].[Na+].[Na+].CNC>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([NH:19][C:20](=[O:21])[N:33]([CH3:34])[CH3:32])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:22]=[N:23][N:24]=[C:11]2[CH2:10][N:9]=1
Reactant: O=C(NCCO)Nc1ccc2c(c1)C(c1ccccc1F)=NCc1nncn1-2
Reactant: O=C=Nc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nncn1-2
Agent: CNC
Agent: Nc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nncn1-2
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)C(=O)Nc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nncn1-2
Reaction time: 25 h

Procedure:
To a solution of [6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-8-yl]isocyanate, prepared as described in paragraph (a) of Example 1 from 7.0 g (22.6 mmol) of 8-amino-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, but using methylene chloride in place of 1,2-dichloroethane, is added in one portion while cooling with ice and stirring a suspension of 8.7 g (81.9 mmol) of sodium carbonate in 5.3 g (117.8 mmol) of dimethylamine and 50 ml of 1,2-dichloroethane. The mixture is left for 25 hours at room temperature and then evaporated at 50° C. in vacuo. The residue is suspended in 300 ml of water, extracted four times with methylene chloride/ethanol (4:1) and the combined organic extracts are subsequently dried and evaporated. Crystallisation from methylene chloride/ethyl acetate yields 3-[6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-8-yl]-1,1-dimethylurea of melting point 180° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[C:3]([O:5][C:6]1[C:7]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH:16]=[O:17])[CH:12]=[CH:11]2)=[O:4].P([O-])(O)(O)=[O:28].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>ClCCl.C(O)(C)(C)C.O>[CH3:1][C:2]([CH3:25])([CH3:26])[C:3]([O:5][C:6]1[C:7]([C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([C:16]([OH:28])=[O:17])[CH:12]=[CH:11]2)=[O:4]
Reactant: O=P([O-])(O)O
Reactant: CCCCOC(=O)c1ccc2ccc(C=O)nc2c1OC(=O)C(C)(C)C
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: CC(C)(C)O
Solvent: O
Product: CCCCOC(=O)c1ccc2ccc(C(=O)O)nc2c1OC(=O)C(C)(C)C
Yield: 64.3 %

Procedure:
A mixture of the preceding aldehyde 4 (step 3) (3.5 g, 10 mmol), sodium dihydrogen phosphate (1.7 g, 12 mmol), 2-methyl-2-butene (6.1 ml, 57 mmol) and sodium chlorite (2.6 g, 29 mmol) is stirred at 20° C. in 160 ml of a 5/1 tert-butanol/water mixture and 30 ml of dichloromethane for 12 hours. The reaction medium is concentrated under reduced pressure. The residue is chromatographed on a silica column, eluting with pure ethyl acetate so as to give 2.4 g (64%) of 8-(2,2-dimethylpropionyloxy)-7-butoxycarbonylquinoline-2-carboxylic acid 5 in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.Cl.[CH3:33][N:34]([CH3:57])[CH2:35][CH2:36][N:37]([C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[N:46]([CH2:52][C:53](O)=[O:54])[C:45]2=[O:56])[S:38]([CH3:41])(=[O:40])=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:53](=[O:54])[CH2:52][N:46]1[C:45](=[O:56])[C:44]2[C:48](=[CH:49][CH:50]=[C:42]([N:37]([CH2:36][CH2:35][N:34]([CH3:33])[CH3:57])[S:38]([CH3:41])(=[O:39])=[O:40])[CH:43]=2)[C:47]1=[O:51]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)O)C2=O)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)CCN(c1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
To a solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (180 mg, 0.428 mmol), DMAP (52.3 mg, 0.428 mmol) and EDC (164 mg, 0.857 mmol) in DCM (10 ml), 2-(5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetic acid hydrochloride (191 mg, 0.471 mmol) was added portion wise within 4 hours, and the reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the crude was purified by flash silica gel chromatography (DCM/MeOH 10/0.2) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a white solid (253 mg, 0.328 mmol, 77% yield). MS/ESI+ 771.15 [MH]+, [αD]=−32.18, c=0.353, DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.93-8.00 (m, 2H), 7.89 (dd, 1H), 7.19 (d, 1H), 7.09 (d, 1H), 6.97 (dd, 1H), 7.08 (t, 1H), 6.02 (dd, 1H), 4.43 (s, 2H), 3.92-4.05 (m, 2H), 3.88 (t, 2H), 3.39 (dd, 1H), 3.23 (dd, 1H), 3.13 (s, 3H), 2.31 (t, 2H), 2.10 (s, 6H), 1.07-1.33 (m, 1H), 0.49-0.71 (m, 2H), 0.27-0.49 (m, 2H)
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2cnccc2c1[N+](=O)[O-]
Solvent: ClCCl
Product: Cc1ccc2c[n+]([O-])ccc2c1[N+](=O)[O-]
Temperature: 0 °C
Yield: 66.3 %

Procedure:
6-Methyl-5-nitroisoquinoline (32 g, 170 mmol) was dissolved in DCM (500 mL) and cooled in an ice-acetone bath to 0° C. 3-Chloroperoxybenzoic acid (49.9 g, 289 mmol) (73%) was added in portions while stirring the reaction mixture vigorously. After the addition, the reaction mixture was stirred at 0° C. for 4 h. Upon being warmed to RT, the reaction mixture was partitioned in DCM/NaOH (aq., 1 N). After multiple extractions, the organic layers were combined and washed with brine then dried over Na2SO4. Removal of the solvent in vacuo gave 6-methyl-5-nitroisoquinoline N-oxide as a yellow solid (23 g). MS (M+H)+205.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:17]O>S(=O)(=O)(O)O.COC(OC)(C)C>[CH3:17][O:15][C:14]([CH:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9]1)=[O:16]
Reactant: CO
Reactant: O=C(O)C1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)OC
Product: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Yield: 84 %

Procedure:
The crude (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid was dissolved in a mixture of 5000 ml of methanol, 24 ml of concentrated sulfuric acid and 400 ml of 2,2-dimethoxypropane and stirred under reflux for 2 h. The reaction solution was reduced to half of its volume by distillation, then transferred into a 20 l vessel. Under stirring at 40° C., a mixture of 2500 ml of water/ice (1:1) was added. Crystallisation started immediately, and, thereupon, the fine white crystals were collected on a filter funnel. They were washed with a total of 2000 ml of cold water until the filtrate was neutral. The product was dried under reduced pressure to yield 980 g (84% of theory, 2 steps) of (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid; MS: m/e=234 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:31]=[C:30]([C:32](=[O:36])[NH:33][CH2:34][CH3:35])[CH:29]=[CH:28][C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][C:17]=1[O:26][CH3:27])(=[O:11])=[O:10].[NH2:37]C(N)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[C:23]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:14]2[CH:28]=[CH:29][C:30]([C:32]([NH:33][CH2:34][CH3:35])=[O:36])=[CH:31][C:13]=2[NH:12][S:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:11])=[C:17]([O:26][CH3:27])[CH:18]=1)(=[O:24])[NH2:37]
Reactant: CCNC(=O)c1ccc(Oc2ccc(CC(=O)O)cc2OC)c(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1
Reactant: NC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCNC(=O)c1ccc(Oc2ccc(CC(N)=O)cc2OC)c(NS(=O)(=O)c2ccc(Cl)cc2Cl)c1
Temperature: 175 °C
Yield: 67.5 %

Procedure:
A mixture of acid 12 (70 mg, 0.126 mmol) and urea (1.0 g, 16.6 mmol) was heated to 170-180° C. and maintained at this temperature for 4 h, and the mixture was allowed to cool. As soon as the temperature dropped to 110-120° C., 2 mL of 5% sodium carbonate aqueous solution was added, and the mixture was shaken vigorously. After mixture was cooled to room temperature, 20 mL of 3N HCl aqueous solution was added and the resulting mixture was extracted with ethyl acetate (4×20 mL). The combined extracts were washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography using EtOAc and 10% CH3OH/EtOAc sequentially as the eluents to give 47 mg of product. 1H NMR (Acetone-d6): δ 8.77 (s, 1H), 8.04 (d, J=2.13 Hz, 1H), 7.96 (d, J=8.57 Hz, 1H), 7.70 (, br s, 1H), 7.63 (d, J=2.13 Hz, 1H); 7.56 (dd, J=8.53, 2.13 Hz, 1H), 7.51 (dd, J=8.53, 2.13 Hz, 1H), 7.11 (d, J=1.86 Hz, 1H), 6.88 (dd, J=8.13, 1.87 Hz, 1H), 6.85 (br s, 1H), 6.75 (d, J=8.13 Hz, 1H), 6.659 (d, J=8.67 Hz, 1H), 3.67 (s, 3H), 3.51 (s, 2H), 3.38 (m, 2H), 1.17 (dd, J=7.20, 7.20 Hz, 3H). LCMS (ESI−) 551 (M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>CN(C)C=O>[CH2:10]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 49.7 %

Procedure:
A mixture of 15 g 4-piperidinecarboxamide, 16.3 g benzyl chloride, 32.3 g potassium carbonate and 200 ml N,N-dimethylformamide was stirred at 80° C. for 4 hr. The reaction solution was returned to room temperature, and aqueous sodium hydroxide was added thereto, and then it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then evaporated. The resulting crystalline residue was washed with hexane/ethyl acetate and collected by filtration. 12.7 g of 1-benzyl-4-piperidine carboxamide was obtained as white flaky crystals.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:3][CH2:2]1.O1CCOCC1.[ClH:35]>CC(OC)(C)C>[ClH:35].[CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN(C(=O)OCc3ccccc3)C2)CC1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a 20 L temperature controlled reactor with jacket set at 0° C., add a solution of O4-benzyl O9-tert-butyl 4,9-diazaspiro[5.5]undecane-4,9-dicarboxylate (2.06 moles; 838.00 g; 95.65% purity) in 1,4-dioxane (19.63 moles; 1.68 L). When the temperature of the solution is 5° C., add hydrogen chloride (4 M in 1,4-dioxane; 10.32 moles; 2.58 L) at such a rate that the temperature does not rise above 20° C. When the addition is complete, warm the solution to room temperature and stir overnight. Concentrate the reaction mixture under reduced pressure to give a thick slurry. Add MTBE (3.35 L) and agitate the mixture for 30 minutes at 40° C. Allow the mixture to cool to room temperature and filter the precipitate. Wash the precipitate with MTBE (838 mL). Allow the precipitate to dry on the filter and then transfer to a vacuum oven for further drying to give the title compound (638 g; 95% yield) mass spectrum (m/z):289 [M(freebase)+1].
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:10][C@H:9]([O:11]CC2C=CC=CC=2)[CH2:8][C@H:7]1[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CCOc1ccc(C)cc1CCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(C)cc1CCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
1820 mg of (2R,4R)-1-ethoxycarbonyl-4-benzyloxy-2-{2-[4-methyl-2-(2-phenylethyl)phenoxy]ethyl}pyrrolidine [prepared as described in step (a) above] were dissolved in 20 ml of ethanol, and then 200 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The resulting mixture was then stirred under a hydrogen atmosphere at atmospheric pressure and at 60° C. for 2 hours. At the end of this time, the catalyst was removed by filtration, and the reaction mixture was concentrated by evaporation under reduced pressure. The resulting concentrate was purified by silica gel column chromatography, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 1410 mg (yield 95%) of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[CH3:24][N:25]([CH3:30])[CH2:26][C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:27](=[O:28])[CH2:26][N:25]([CH3:30])[CH3:24])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Product: CN(C)CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 19, with the exceptions that 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that N,N-dimethyl glycine was used instead of N-Boc glycine.
Reaction SMILES: C([BH3-])#N.[Na+].C1(N2[C:15]([CH2:16][O:17]C)=[C:14]([C:19]3ON=[C:21]([C:24]4C=CC(C=O)=CC=4)[N:20]=3)C=N2)CCCCC1.C(O)(=[O:34])C>CO>[NH:20]1[CH2:19][CH2:14][CH:15]([C:16]([OH:17])=[O:34])[CH2:24][CH2:21]1
Reactant: COCc1c(-c2nc(-c3ccc(C=O)cc3)no2)cnn1C1CCCCC1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)C1CCNCC1

Procedure:
Sodium cyanoborohydride (32.5 mg; 0.517 mmol) was added to a solution of 4-(5-(1-cyclohexyl-5-(methoxymethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained from step 1, (172 mg; 0.47 mmol) and isonipecotic acid (121.4 mg; 0.94 mmol) in a mixture of methanol (3 mL) and acetic acid (80.7 μl; 0.141 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC to give Example 64 as a white solid. 1H NMR (DMSO-d6) δ 8.23 (1 H, s), 8.04 (2 H, d, J=8.1 Hz), 7.54 (2 H, d, J=8.0 Hz), 5.02 (2 H, s), 4.44-4.34 (1 H, m), 3.56 (2 H, s), 3.34 (3 H, s), 2.78 (2 H, d, J=11.0 Hz), 2.26-2.17 (1 H, m), 2.06 (2 H, t, J=11.2 Hz), 1.96-1.76 (8 H, m), 1.71 (1 H, d, J=12.8 Hz), 1.66-1.52 (2 H, m), 1.53-1.37 (2 H, m), 1.25 (1 H, t, J=13.0 Hz). LC/MS: 480 (M+H)+. HPLC (Method G) Rt=2.39 min (Purity: 96.7%).