Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:28])[CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1>>[CH3:27][O:26][C:24]1[CH:23]=[C:22]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:21]=[C:20]([O:19][CH3:18])[CH:25]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: COc1cc(Nc2nc(Nc3cc[nH]n3)cc3ccccc23)cc(OC)c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,5-dimethoxy-phenylamine to give N1-(3,5-dimethoxy-phenyl)-N3-(1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 362(MH+).
Reaction SMILES: [CH3:1][CH:2]([CH:8]=[O:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>CCOCC>[CH2:10]1[CH2:11][O:12][CH:8]([CH:2]([CH3:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[O:9]1
Reactant: COC(=O)CC(C)C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)CC(C)C1OCCO1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-methyl-4-oxo-butanoate (86.3 g), ethylene glycol (61.75 l g, 0.996 m), p-toluenesulfonic acid (1 g) and benzene (700 ml) is refluxed under nitrogen for 16 hr. The resulting mixture is allowed to cool to room temperature and treated with ether (300 ml). The organic phase is washed with 5% sodium bicarbonate solution (100 ml), dried (Na2SO4) and evaporated in vacuo to give methyl 4,4-ethylenedioxy-3-methylbutanoate as a crude product (63.2 g). This material is used directly in the next step.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].O[CH:14]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:16]2[N:27]([CH3:30])[N:28]=[CH:29][C:15]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH:14]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:17][C:16]2[N:27]([CH3:30])[N:28]=[CH:29][C:15]1=2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1ncc2c1CN(C(=O)OC(C)(C)C)CC2ON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a mixture of 2-hydroxy-1H-isoindole-1,3(2H)-dione (2.95 g, 18.1 mmol), tert-butyl 4-hydroxy-1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate 135 (US2005/245505 A1, 2.29 g, 9.04 mmol) and triphenylphosphine (4.74 g, 18.1 mmol) in THF (100 mL) was added DIAD (3.85 mL, 19.9 mmol) slowly at room temperature. The resulting mixture was stirred at room temperature overnight and concentrated to provide a residue which was subjected to chromatography to give 136 (2.5 g, 35%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([C@H:18]3[CH2:21][C@H:20]([O:22]CC4C=CC=CC=4)[CH2:19]3)[C:16]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)[C:16]3[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1[C@H]1C[C@H](OCc2ccccc2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)cc2n1C1CC(O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 157 %

Procedure:
4-Amino-6-[(S)-1-[1-(trans-3-benzyloxycyclobutyl)-6-fluoro-1H-benzoimidazol-2-yl]ethylamino]-pyrimidine-5-carbonitrile (0.06 g, 0.13 mmol) in DCM (5 mL) cooled to 0° C. To this mixture was added boron tribromide (1M solution in DCM, 0.26 mL, 0.23 mmol) dropwise and the resulting mixture stirred at RT for 2 h. The reaction mixture was quenched with MeOH (2 mL) and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford 392 as a colourless glassy solid (75 mg, quantitative). LCMS (Method K): RT 2.41 min [M+H]+ 368.3. 1H NMR (DMSO-d6): δ 8.17 (1H, d, J=6.44 Hz), 8.07 (1H, s), 7.92 (1H, d, J=9.28 Hz), 7.81 (1H, dd, J=8.98, 4.77 Hz), 7.59 (2H, s), 7.41 (1H, t, J=9.27 Hz), 5.83-5.75 (1H, m), 5.49-5.39 (1H, m), 4.59-4.53 (1H, m), 3.16-2.97 (2H, m), 2.46-2.28 (2H, m), 1.67 (3H, d, J=6.81 Hz
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:26]1([C:35]#[N:36])[CH2:29][N:28]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:27]1.C(O)(=O)C>C1COCC1.[Zn]>[CH:32]1([C:30]([N:28]2[CH2:29][C:26]([C:3]3[CH:2]=[CH:7][C:6]([C:8]4[CH2:12][C:11]([C:17]5[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=5)([C:13]([F:15])([F:14])[F:16])[O:10][N:9]=4)=[CH:5][CH:4]=3)([C:35]#[N:36])[CH2:27]2)=[O:31])[CH2:34][CH2:33]1
Reactant: N#CC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2Br)CN(C(=O)C2CC2)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CC1(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)CN(C(=O)C2CC2)C1
Reaction time: 0.03 h

Procedure:
The compound of Example 86 (60 mg) was dissolved in THF (2 mL) and Rieke Zn in THF was then added dropwise (2 mL of a 0.7N solution). The mixture was then sonicated for 5 minutes. LC-MS (THF+a few drops of acetic acid) shows about 50% conversion. Another 4 equivalents of Zn was added, and again 15 minutes sonication. LC-MS shows the reaction mixture is gone to about 90% conversion. About 200 μL of acetic acid was then added, the reaction mixture was stirred for 2 minutes, then filtered over celite. The solution was concentrated under vacuum and the remaining oil dissolved in ethyl acetate and washed with NaHCO3, then dried over MgSO4, filtered and concentrated in vacuum. The remaining oil is purified via reverse phase chromatography. Yield 55 mg. LC-MS confirms desired product [m/z 542]. NMR 400 MHz δ ppm: 7.78 (d, 2H), 7.67 (d, 2H), 7.66 (s, 2H), 4.99 (m, 1H), 4.71 (m, 1H), 4.53 (m, 1H), 4.39 (m, 1H), 4.10 (d, 1H), 3.71 (d, 1H), 1.45-1.39 (m, 1H), 1.10-1.06 (m, 2H), 0.91-0.86 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][OH:24])[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][O:24][S:34]([CH3:33])(=[O:36])=[O:35])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2COS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
[3-(2-Hydroxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.355 g, 1.0 mmol) and triethylamine (0.21 mL, 1.5 mmol) were combined in CH2Cl2 (7.2 mL) and cooled to 0° C. Methanesulfonyl chloride (0.09 mL, 1.1 mmol) was added, and the reaction was stirred for 3 hours. Some starting material was still seen by analytical LCMS, so additional methanesulfonyl chloride (0.04 mL) and triethylamine (0.07 mL) was added at 0° C., and the reaction was stirred for another 2 hours. The mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([CH2:21][C:22]1[CH:27]=[N:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[C:24]2[O:32]C(C)(C)[O:34][CH2:35][C:23]=12)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O>[CH2:1]([O:8][CH2:9][CH2:10][N:11]([CH2:21][C:22]1[C:23]([CH2:35][OH:34])=[C:24]([OH:32])[C:25]([C:28]([O:30][CH3:31])=[O:29])=[N:26][CH:27]=1)[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ncc(CN(CCOCc2ccccc2)CCc2ccc(F)cc2)c2c1OC(C)(C)OC2
Solvent: O=CO
Product: COC(=O)c1ncc(CN(CCOCc2ccccc2)CCc2ccc(F)cc2)c(CO)c1O

Procedure:
Methyl 5-(((2-(benzyloxy)ethyl)(4-fluorophenethyl)amino)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (compound 26a) was reacted with formic acid according to the procedure described in example 21 step 21b. MS-ESI m/z 469 [MH]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][NH2:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][NH:12][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)Cl
Reactant: NCCc1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NCCc1ccc2[nH]ccc2c1
Reaction time: 0.33 h

Procedure:
A mixture of 1H-indole-5-ethanamine (1.00 g), methane sulphonylchloride (0.69 ml), 8% sodium bicarbonate solution (100 ml) and ethyl acetate (100 ml) were stirred vigorously for 20 min. The organic phase was separated and the aqueous phase extracted with ethyl acetate (50 ml). The combined organic phases were dried and evaporated in vacuo to give the title compound as an oil (1.50 g). T.l.c. SiO2, EtOAc Rf 0.8
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:13][CH:10]2[CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: NC1CC1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Clc1ncc(Br)c(NC2CC2)n1

Procedure:
In analogy to compound 1.1, a solution of 1.0 g (4.39 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 15 ml of acetonitrile is reacted with 0.27 g (4.74 mmol) of cyclopropylamine in the presence of 0.74 ml (5.3 mmol) of triethylamine. Purification by chromatography (silica gel, ethyl acetate/hexane with ethyl acetate 0-100%) results in 0.76 g (70% of theory) of the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[N:26]=CN(C)C)[CH2:10][C:9]1=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(NN)(=O)=O)=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:15]2[CH2:16][C@H:11]([CH2:12][CH2:13][C@@H:14]2[N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][CH:20]=[N:21][C:22]=3[NH2:26])[CH2:10][C:9]1=[O:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=Nc1ncnc2c1ncn2[C@H]1CC[C@@H]2CC(=O)N(C(=O)OC(C)(C)C)[C@H]1C2
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)C[C@H]2CC[C@H](n3cnc4c(N)ncnc43)[C@@H]1C2
Temperature: 25 °C
Reaction time: 44 h
Yield: 85.9 %

Procedure:
A 250 ml round-bottomed flask was loaded with 6.64 g of amidine A lactam 15d (15.5 mmol) and 150 ml of dry CH2Cl2. 11.55 g of p-toluenesulphonic acid hydrazide (62.0 mmol) were then added followed by 1.47 g of TsOH (7.75 mmol). The solution was stirred at room temperature for 44 h. After the addition of 150 ml of CH2Cl2, the solution was washed three times with water and adjusted to a pH of >12 by addition of 2M NaOH. The combined wash solutions were extracted with 100 ml of CH2Cl2 and the combined organic phases dried over MgSO4. After filtration, the solvent was removed under reduced pressure and the resulting residue was purified by means of chromatography (5.2×20 cm silica gel, eluent: CHCl3/MeOH 30:1) to afford 4.96 g of 15e (86%), which is sufficiently pure for further reactions. An analytical sample was obtained by crystallization from THF/cyclohexane.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([F:39])([CH3:38])[CH3:37])[CH2:16]1)=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(F)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)F)CN1C(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 85.3 %

Procedure:
Add acetic anhydride (0.084 mL, 0.91 mmol) to a solution of (2S,5R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-(2-fluoro-2-methylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (400 mg, 0.86 mmol) and triethylamine (0.81 mL, 130 mmol) in dry dichloromethane (10 mL) at room temperature and stir for 4 hours, concentrate and purify (silica gel cartridge chromatography, eluting with 2:1 to 1:2 hexanes:ethyl acetate), to give the desired compound as a white solid (0.37 g, 80%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]([C:34]1[N:39]=[CH:38][C:37]([C:40](C)(C)[O:41][SiH2]C(C)(C)C)=[CH:36][N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24]([N:26]([C:34]1[N:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C(C)(C)O[SiH2]C(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(CO)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
Tetrabutylammonium fluoride (15.3 g, 48.6 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-(ter-butyl-dimethyl-silanyloxymethyl)-pyrimidin (10.0 g, 24.3 mmol) in THF (100 mL) and stirred at room temperature overnight. Water was added and the product extracted with chloroform. The organic phase was dried and concentrated under reduced pressure. Flash chromatography (MeOH/CH2Cl2, 2.5:77.5) gave 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-pyrimidin (4.20 g, 53%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[O:7][C:8]([C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:9]([N:23]1[C@H:26](SCC)[C@@H:25]([C@H:30]([OH:32])[CH3:31])[C:24]1=[O:33])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[S:11])([OH:3])=[O:2].[Cl:43]Cl>[2H]C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:40]=[CH:41][CH:42]=1)[O:7][C:8]([C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:9]([N:23]1[C@@H:26]([Cl:43])[C@@H:25]([C@H:30]([OH:32])[CH3:31])[C:24]1=[O:33])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[S:11])([OH:3])=[O:2]
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1cccc(C(=O)O)c1)C(=O)C(C)(C)C
Reactant: ClCl
Agent: [2H]C(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2cccc(C(=O)O)c2)C(=O)C(C)(C)C)[C@H]1Cl
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To a stirred solution of 5.5 g of 4-nitrobenzyl 3-(3-carboxyphenoxy)-2-(4(R)-ethylthio-3(S)-[1(R)-hydroxyethyl]azetidin-2-on-1-yl)-3-trimethylacetylthiopropenoate in 50 ml of dry deuterochloroform at -40° C. was added a solution of 10.6 mmol of chlorine in carbon tetrachloride. The mixture was stirred for a further 30 minutes at -40° C., and for 30 minutes at room temperature, and was evaporated in vacuo. Chromatography of the residue over silica gel, and elution with hexane-ethyl acetate-formic acid mixtures afforded 4.6 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][CH:42]=[C:43]([CH:46]=2)[C:44]#[N:45])O1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:39]4[CH:40]=[N:41][CH:42]=[C:43]([CH:46]=4)[C:44]#[N:45])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7]2)[N:6]=1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cncc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 29.4 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (24 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 5-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)nicotinonitrile (6.27 mg, 30%). 1H-NMR (MeOD): 2.04 (d, 1H), 2.20 (m, 1H), 3.06 (m, 3H), 5.24 (d, 0.3H), 5.82 (d, 0.7H), 7.01 (m, 1H), 7.36 (m, 6H), 7.50 (m, 1H), 8.29 (m, 1H), 8.70 (m, 1H), 8.89 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2([CH2:16][CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1>CO.[Pd]>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[CH2:11][C:2]1=[O:1]
Reactant: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc2N1
Agent: [Pd]
Solvent: CO
Product: O=C1CC2(CCNCC2)c2ccccc2N1
Reaction time: 3 h
Yield: 15 %

Procedure:
The mixture of benzyl 2′-oxo-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1-carboxylate (1.2 g, 3.4 mmol) and Pd/C (200 mg) in MeOH (20 mL) was hydrogenated under atmosphere pressure at room temperature for 3 h. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC twice to give 1′H-spiro[piperidine-4,4′-quinolin]-2′(3′H)-one (110 mg, 11%) as a TFA salt. 1H NMR (CDCl3) δ 7.65 (d, J=7.5 Hz, 1H), 7.29-7.45 (m, 3H), 3.45 (d, J=12.3 Hz, 2H), 3.20 (t, J=12.3 Hz, 2H), 2.96 (s, 2H), 2.10-2.21 (m, 2H), 1.70 (d, J=14.1 Hz, 2H). MS (ESI) m/z 217.06 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:8])OC.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13]2.Cl>C1COCC1>[CH3:3][O:4][C:5]([CH:14]1[CH2:13][C:12]2[C:16](=[CH:17][CH:18]=[C:10]([F:9])[CH:11]=2)[CH2:15]1)=[O:8]
Reactant: COC(=O)OC
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1Cc2ccc(F)cc2C1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
To a mixture of NaH (2.64 g, 66 mmol) in dimethylcarbonate (4.2 mL, 50 mmol) in THF (30 mL) was added a solution of 5-fluoroindanone (commercially available from Aldrich) (5 g, 33 mmol). After 30 m at 65° C. the mixture was cooled to rt, acidified with HCl (aq) and extracted with Et2O or EtOAc. The organic layers were washed with water, dried over MgSO4 and evaporated to dryness. The residue was used in the next step without further purification. The keto-ester was dissolved in AcOH (100 mL) and 70% perchloric acid (2 mL). 10% Pd/C (2 g) was added and the mixture was hydrogenated at 50 psi for 18 h. The mixture was diluted with Et2O or CHCl3 and water and filtered through a pad of celite. The organic layer was separated and the aqueous layer was extracted with Et2O. The organic fractions were pooled, washed with water, dried over MgSO4, filtered and evaporated to leave a residue. The residue was purified by chromatography on silica gel with 15% EtOAc:hexane to give 5-fluoro-indan-2-carboxylic acid methyl ester (Intermediate EIGHTEEN-3), 2.25 g. Use of 5-fluoro-indan-2-carboxylic acid methyl ester (Intermediate EIGHTEEN-3) in Method SEVENTEEN produced 4-(5-fluoro-indan-2-yl)-1,3-dihydro-imidazole-2-thione (Compound 145).
Reaction SMILES: CS(C)=O.[CH3:5][N:6]([CH3:12])[C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:30])[CH2:27][CH2:28][CH3:29])=[O:25])[O:23][C:19]=2[C:18](F)=[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:16]=1[CH3:38])#[N:14].C(N(CC)CC)C>[Cl-].[Na+].O>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([N:26]([CH3:30])[CH2:27][CH2:28][CH3:29])=[O:25])[O:23][C:19]=2[C:18]([N:9]2[CH2:10][CH2:11][C@H:7]([N:6]([CH3:12])[CH3:5])[CH2:8]2)=[C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:16]=1[CH3:38])#[N:14]
Reactant: CCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Reaction time: 2.33 h
Yield: 43.6 %

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (1 ml) solution of (3S)-3-(dimethylamino)pyrrolidine (49 μl, 383 μmol) was added at 140 to 150° C. to a dimethyl sulfoxide (5 ml) solution of 4-cyano-7-fluoro-N,5-dimethyl-6-phenyl-N-propyl-1,3-benzoxazole-2-carboxamide (I-284) (112 mg, 319 μmol) and triethylamine (58 μl, 415 μmol), followed by stirring at the same temperature for 140 minutes. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under the reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol==10:1, v/v) to obtain the entitled compound (62 mg, 44%) as an amorphous substance.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[C@@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:28])[CH2:18]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[C@@:19]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]([CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[C:20]3=[O:28])[CH2:18]2)=[CH:15][CH:16]=1
Reactant: CCN(CC)CCCl
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Agent: Cl
Product: CCN(CC)CCN1C(=O)[C@@]2(C[C@H]2c2ccc(Cl)cc2)c2ccccc21

Procedure:
The title compound was prepared in analogy to Example 70 starting from 2-Chloro-N,N-diethylethaneamine hydrochloride (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)Spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C22H25ClN20: 368, observed (M+H)+: 369.1 1H NMR (400 MHz, MeOD-d4) δppm 1.41 (t, J=7.20 Hz, 6 H) 2.21-2.31 (m, 2 H) 3.32 (t, J=8.59 Hz, 1 H) 3.39-3.55 (m, 4 H) 3.60 (t, J=6.44 Hz, 2 H) 4.23-4.42 (m, 2 H) 6.16 (d, J=7.58 Hz, 1 H) 6.85 (t, J=7.45 Hz, 1 H) 7.19 (d, J=7.83 Hz, 1 H) 7.24-7.32 (m, 3 H) 7.33-7.40 (m, 2 H).