Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[CH:31]1([NH:34][C:28](=[O:30])[CH2:27][N:25]2[CH:26]=[C:22]([C:19]3[C:16]4[CH:17]=[N:18][C:13]([C:3]5[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=5[Cl:12])=[CH:14][C:15]=4[NH:21][N:20]=3)[CH:23]=[N:24]2)[CH2:33][CH2:32]1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: NC1CC1
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)NC5CC5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and cyclopropylamine. LCMS (M+H)+=487.1/489.1.
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH:14][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Agent: I
Product: Cc1ccc(C(=O)Nc2nc3c(s2)Cc2ccccc2-3)cc1
Yield: 25.5 %

Procedure:
Acylation of 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, 100 mg; 0.32 mmol) with 4-methylbenzoyl chloride (0.0.130 mL; 0.96 mmol) in a manner similar to that described in Example 1, Step 3 provided 25 mg of N-(8H-Indeno[1,2-d]thiazol-2-yl)-4-methyl-benzamide 5. EI-HRMS m/e calcd for C16H11N3OS (M+) 293.0623, found 293.0621.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([OH:18])[CH2:13]1)[CH:6]=[CH:5]2.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[Cl:1][C:2]1[C:3]([NH:19][C:20](=[O:28])[CH2:21][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([O:18][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCC[C@@H](O)C3)ccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reaction time: 24 h

Procedure:
To a stirred solution of N-[6-chloro-2-[(3R)-3-hydroxy-1-piperidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 37) (0.715 g) in dichloromethane (10 mL) was added triethylamine (0.99 mL) followed by methanesulfonyl chloride (0.275 mL). The reaction was stirred under nitrogen for 24 hours followed by the removal of volatiles under vacuum. The resulting mixture was taken up in methanol (20 mL) and placed down a Varian® SCX cartridge, washed with methanol (50 mL) and eluted with ammonia in methanol (0.7M, 50 mL). The solvent was removed to afford the sub-titled compound (0.64 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10].C(OC([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:38]([C@H:34]4[CH2:35][CH2:36][CH2:37][NH:33]4)=[O:39])[CH2:24][CH2:25]3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCNCC3)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a stirred solution of the crude (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(piperazin-1-yl)-1H-benzo[d]imidazole (0.10 g, 0.27 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.064 g, 0.32 mmol) in dichloromethane (2 mL) was added HATU (0.12 g, 0.32 mmol) and triethylamine (Et3N, 0.2 mL, 1.4 mmol). The reaction mixture was stirred at room temperature for 2 h, and diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% methanol in dichloromethane) to afford the desired product (0.11 g, 0.19 mmol, 71% for 2 steps).
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[OH:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31]>CN1CCCC1=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][O:11][CH2:10][CH2:9][O:20][N:21]1[C:22](=[O:31])[C:23]2=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]2[C:25]1=[O:26]
Reactant: Fc1ccccc1COCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCCOCc1ccccc1F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
108 ml of triethylamine were added dropwise to a mixture of 165 g (0.71 mol) of 1-bromo-2-(2-fluorobenzyloxy)-ethane, 116 g (0.7 mol) of N-hydroxylphthalimide and 710 ml of N-methyl-2-pyrrolidinone at from 20° to 25° C. in the course of 1 hour. After 5 hours at 60° C., the cold reaction mixture was poured into 200 ml of ice water and the precipitate was filtered off under suction, washed with water and isopropanol and dried under reduced pressure over phosphorus pentoxide.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:118])[C:82]2[CH:81]=[C:80]([C:83]3[CH:84]=[CH:85][C:86]4[N:90]=[C:89]([C@@H:91]5[CH2:95][CH2:94][CH2:93][N:92]5[C:96](=[O:106])[C@@H:97]([NH:101][C:102](=[O:105])[O:103][CH3:104])[CH:98]([CH3:100])[CH3:99])[NH:88][C:87]=4[CH:107]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:108]1[NH:112][C:111]([C@@H:113]3[CH2:117][CH2:116][CH2:115][NH:114]3)=[N:110][CH:109]=1)=[CH:74][CH:75]=2>>[CH3:104][O:103][C:102](=[O:105])[NH:101][C@@H:97]([CH:98]([CH3:100])[CH3:99])[C:96]([N:92]1[CH2:93][CH2:94][CH2:95][C@H:91]1[C:89]1[NH:88][C:87]2[CH:107]=[C:83]([C:80]3[CH:79]=[CH:78][C:77]4[C:76]5[C:71](=[CH:72][C:73]([C:108]6[NH:112][C:111]([C@@H:113]7[CH2:117][CH2:116][CH2:115][N:114]7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=[N:110][CH:109]=6)=[CH:74][CH:75]=5)[C:70]([F:69])([F:118])[C:82]=4[CH:81]=3)[CH:84]=[CH:85][C:86]=2[N:90]=1)=[O:106]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc3-4)cc2[nH]1)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-1-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 871.95 [M+H]+. (174 mg, 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([CH2:33][O:34][CH2:35][O:36][CH3:37])([CH2:30][C:31]#[CH:32])[C:26]([O:28]C)=[O:27])=[C:18]([Cl:38])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C1COCC1.[OH-].[Na+]>O.Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][C:25]([CH2:33][O:34][CH2:35][O:36][CH3:37])([CH2:30][C:31]#[CH:32])[C:26]([OH:28])=[O:27])=[C:18]([Cl:38])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCC(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(COCOC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#CCC(CCCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(COCOC)C(=O)O
Reaction time: 20 h
Yield: 99.9 %

Procedure:
The compound of Example 214 (1.12 g) was dissolved in a mixed solvent composed of MeOH:THF=1:1 (12 mL). To this solution, a 10% aqueous solution of sodium hydroxide (4 mL) was added and the mixture was refluxed. After 20 hours, the mixture was diluted with water, and hydrochloric acid was added to make the mixture acidic. The mixture was then extracted with ethyl acetate and the extract was washed with a saturated aqueous solution of sodium chloride. The organic phase was then dried over anhydrous magnesium sulfate. The solvent was removed to give the desired product as a yellow oil (1.09 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][NH2:17].C(O)(=O)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([NH:17][CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCN(Cc2ccccc2)CC1=O
Reactant: CN
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC1CN(Cc2ccccc2)CCC1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.75 %

Procedure:
To a stirred solution of the product from Method E (3.81 grams/0.019 mol) and 38 mL of 2.0 M methylamine in THF was added 2.2 mL of acetic acid and the resulting mixture stirred at room temperature for 1.5 hours. Triacetoxysodiumborohydride (NaB(OAc)3H) (7.94 grams/0.038 mol) was added as a solid and the new mixture stirred at room temperature for 18 hours. The reaction was quenched with 2 N hydrochloric acid and the pH adjusted to 1. The reaction mixture was washed two times with ether, the aqueous layer then adjusted to pH of 12 with 6 N sodium hydroxide (aq) and extracted three times with dichloromethane The combined dichloromethane layers were dried over Na2SO4, filtered and evaporated to dryness in vacuo affording 3.51 grams (87.75%) of the title compound as dark yellow oil. LRMS: 219.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:27]=[CH:26][C:11]3[C:12]4[N:16]([CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:13]=4)[CH2:2]1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O.O.CC(O)=O>[CH:29]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([O:7][C:8]2[CH:27]=[CH:26][C:11]3[C:12]4[N:16]([CH:15]=[C:14]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[N:13]=4)[CH2:17][CH2:18][O:19][C:10]=3[CH:9]=2)[CH2:2]1)([CH3:31])[CH3:28]
Reactant: c1ccc(-c2cn3c(n2)-c2ccc(OC4CCCNC4)cc2OCC3)nc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)N1CCCC(Oc2ccc3c(c2)OCCn2cc(-c4ccccn4)nc2-3)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 8-(piperidin-3-yloxy)-2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene from Example 9 (13 mg, 0.036 mmol) in DCM (1 mL) were added acetone (100 uL), AcOH (50 uL) and sodium triacetoxyborohydride (15 mg, 0.072 mmol). The resulting mixture was stirred at RT for 18 h and then diluted with EtOAc. The organic layer was poured into water and the aqueous layer basified with a saturated solution of NaHCO3. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 218 as a white solid (11 mg, 76%). LCMS: RT 2.05 min [M+H]+ 405.1. 1H NMR (CDCl3, 400 MHz): δ 8.57-8.51 (2H, m), 8.09 (1H, dt, J=7.95, 1.07 Hz), 7.72 (1H, td, J=7.72, 1.83 Hz), 7.61 (1H, s), 7.16-7.10 (1H, m), 6.75 (1H, dd, J=8.99, 2.58 Hz), 6.57 (1H, d, J=2.55 Hz), 4.50-4.45 (2H, m), 4.43-4.32 (3H, m), 3.13-3.07 (1H, m), 2.85-2.70 (2H, m), 2.26-2.10 (3H, m), 1.86-1.78 (1H, m), 1.48-1.36 (1H, m), 1.26 (1H, s), 1.04 (6H, d, J=6.57 Hz)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[S:16][CH2:15][CH2:14][C:9]3([S:13][CH2:12][CH2:11][S:10]3)[C:6]=2[C:7]=1[CH3:8].C([Li])CCC.[C:23](=[O:25])=[O:24]>O1CCCC1.CCCCCC>[CH3:8][C:7]1[C:6]2[C:9]3([CH2:14][CH2:15][S:16][C:5]=2[C:4]([CH3:17])=[CH:3][C:2]=1[C:23]([OH:25])=[O:24])[S:13][CH2:12][CH2:11][S:10]3
Reactant: O=C=O
Reactant: Cc1cc(Br)c(C)c2c1SCCC21SCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(C(=O)O)c(C)c2c1SCCC21SCCS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound of Step A (2.7 g, 7.7 mmol) in tetrahydrofuran (20 mL) under a nitrogen atmosphere cooled to -78° C. was added n-butyllithium (Aldrich, 4.6 mL, 11.5 mmol of a 2.5 M solution in hexane) dropwise while maintaining the temperature below -60° C. After stirring for 2 h, excess carbon dioxide (dry ice) was added. The resulting mixture was allowed to warm to room temperature and was left at room temperature overnight. To this reaction mixture was added hexanes (30 mL), and the mixture was filtered. The solid was added to a mixture of water:methylene chloride (20 mL:20 mL), cooled to about 0° C., and acidified to pH 1 with concentrated hydrochloric acid. The organic layer was separated, and aqueous layer was extracted with diethyl ether (3×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to about 10 mL. A white solid precipitated and this solid was isolated by filtration to afford the title compound of Step B (1.62 g) as a solid melting at 236-238° C. 1H NMR (Me2SO-d6): δ2.17 (s,3H), 2.68 (m,2H), 2.81 (s,3H), 3.11 (m,2H), 3.50-3.70 (4H), 7.33 (s,1H), 12.78 (s,1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CC(C)=O>[Cl:15][CH2:16][CH2:17][C:18]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:19]
Reactant: Nc1cccc(F)c1
Reactant: O=C(Cl)CCCl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1cccc(F)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3-fluoroaniline (10 g, 90.00 mmol) in acetone (40 ml) was added pyridine (18 g, 227.56 mmol) and 3-chloropropanoyl chloride (13.73 g, 108.14 mmol) and the reaction was stirred for 3 h at 55° C. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 3-chloro-N-(3-fluorophenyl)propanamide as a yellow solid (13.21 g, 73%).
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[CH3:9][O:10][CH:11]([O:16][CH3:17])[CH2:12][CH2:13][C:14]#[N:15].C(Cl)Cl>C1COCC1.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:14]([NH2:15])[CH2:13][CH2:12][CH:11]([O:16][CH3:17])[O:10][CH3:9])=[O:5]
Reactant: COC(CCC#N)OC
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(CCC(N)=C(SC)S(C)=O)OC
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 76.5 %

Procedure:
2.370 Grams of methyl methylthiomethyl sulfoxide was dissolved in 20 ml of anhydrous THF, and to which 475 mg of sodium hydride was added under cooling with ice, followed by 50 minutes' stirring at 0°C. and additional 50 minutes' stirring at room temperature. Again icecooling the system, 3.73 ml of 4,4-dimethoxybutyronitrile was added dropwise, followed by 18 hours' stirring and further 23 hours' stirring at 50° - 55°C. The reaction liquid was again cooled with ice while 30 ml of methylene chloride and 1 ml of water were added thereto, and after a little while the temperature was returned to the normal level, followed by 3 hours' stirring. After an overnight's drying with Glauber's salt, the reaction mixture was filtered, and the solvent was evaporated off under reduced pressure. The residue was parted by a column chromatography (Florisil, methylene chloride, ethyl acetate and methanol), to allow the recovery of 457 mg of methyl methylthiomethyl sulfoxide and 4.332 g of a crystalline product. The crystals were dissolved in hot methylene chloride, and the insoluble matter was removed by filtration. The filtrate was concentrated under a reduced pressure to leave 3.70 g of 1-methylsulfinyl-1-methylthio-2-amino-5,5-dimethoxy-1-pentene in light yellow, crystalline form. The yield was 76.5%, and the conversion yield was 94.8%.
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H:10]([CH3:26])[NH:11][CH:12]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.[H][H]>C(O)C.C(O)(=O)C.[Pd]>[CH2:24]([O:23][C:21]([CH:12]([NH:11][C@H:10]([C:9]([OH:27])=[O:8])[CH3:26])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)O

Procedure:
N-(1-Ethoxycarbonyl-3-Phenylpropyl)-L-Alanine Benzylester (4.2 g) is dissolved in 40 ml ethanol, to which is added 630 mg 10% Pd-C and a few drops of acetic acid. Hydrogenation occurs under a 30 psi hydrogen atmosphere at room temperature overnight. The resulting mixture is filtered through celite and dried under vacuum to remove the solvent, yielding a residue. The residue is partitioned between chloroform and aqueous 5% NaHCO3, separated, and the chloroform layer further washed with aqueous 5% NaHCO3. The aqueous layers are combined, acidified to pH 3.5 with dilute HCl, extracted with chloroform or ethylacetate several times, dried over MgSO4, and placed under vacuum to evaporate the solvent and yield 2.5 g of the diastereoisomeric product, a brown sticky solid [TLC (Silica gel; CHCl3 /MeOH/HOAC=9:1:0.5); Rf=0.4].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([C:23]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[C:17]([NH2:24])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:25])[N:11]=[C:10]([F:26])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[Cl:25][C:12]1[N:11]=[C:10]([F:26])[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([C:23]5[C:18](=[N:19][CH:20]=[CH:21][CH:22]=5)[C:17]([NH2:24])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:27]1[C:29]([F:32])=[N:11][CH:10]=[CH:9][CH:14]=1)=[CH:7][CH:6]=3
Reactant: NC1=N[C@]2(c3cc(Br)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@]2(c3cc(-c4cccnc4F)ccc3Oc3c2cc(Cl)nc3F)c2cccnc21

Procedure:
The titled compound was synthesized by procedures and steps analogous to those described in Example 5 above, but using (S)-7-bromo-3-chloro-1-fluorospiro[chromeno[2,3-c]pyridine-5,5′-pyrrolo[3,4-b]pyridin]-7′-amine (17c-2) in step 3. MS m/z=448.0 [M+H]+. Calculated for C23H12ClF2N5OC2HF3O2: 561.85 (TFA salt).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:38]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37](=[O:38])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(=O)c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.5 g), sodium hydride (0.25 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 10 min, 2-bromo-1-phenylethanone (1.25 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.87 g, 43%).
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46](Br)[CH:47]=1)[CH3:38]>>[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46]([C:27]2[CH:26]=[CH:25][C:17]([C:18](=[O:19])[NH:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:16][C:15]=2[CH2:14][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([CH:11]2[CH2:12][CH2:13]2)=[O:10])[CH:47]=1)[CH3:38]
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CC(C)(C)NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Product: CCOC(=O)Cc1cncc(-c2ccc(C(=O)NC(C)(C)C)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-N-tert-butyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 3, Step 6 to provide (5-{2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-tert-butylcarbamoyl-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:13]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[C:12]([CH3:11])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Yield: 90.2 %

Procedure:
Using 4-bromobenzoic acid (0.50 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (0.48 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (0.84 g) was obtained.