Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:27][CH2:26]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5]
Reactant: CC(C)(C)OC(=O)NCC1CCC(N)CC1
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC1CCC(NCc2ccc(Cl)c(C(=O)NCC34CC5CC(CC(C5)C3)C4)c2)CC1
Yield: 52.8 %

Procedure:
Prepared according to the method described in Example 31b from 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.30 g, Example 31a), [(4-aminocyclohexyl)methyl]-carbamic acid, 1,1-dimethylethyl ester (0.207 g, WO 97/32882), sodium triacetoxyborohydride (0.135 g) and 1,2-dichloroethane (10 ml). The residue was purified by chromatography over silica gel eluting with ethyl acetate: iso-hexane (1:1) then ethyl acetate: ethanol (9:1) to give the subtitle compound as a colourless oil (0.26 g).
Reaction SMILES: [C:1]([N:5]1[C:9]2[C:10](=[O:26])[NH:11][C:12]3([CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)[CH2:13][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[ClH:27]>C(OCC)(=O)C.O1CCOCC1>[ClH:27].[C:1]([N:5]1[C:9]2[C:10](=[O:26])[NH:11][C:12]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:13][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cnn(C(C)(C)C)c1C(=O)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)n1ncc2c1C(=O)NC1(CCNCC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1′-tert-butyl-7′-oxo-1′,4′,6′,7′-tetrahydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridine]-1-carboxylate (137 mg, 0.39 mmol) in ethyl acetate (4 mL) was added 4 N HCl in dioxane (2 mL). After stirring 1 hour at room temperature, the volatiles were removed under reduced pressure and the resultant colorless solid was triturated from heptane (10 mL) to yield 112 mg of the title compound as a colorless solid. +APCI (M+H) 263.3; 1H NMR (400 MHz, DMSO-d6, δ): 8.84 (m, 2H), 8.00 (s, 1H), 7.29 (s, 1H), 3.13 (d, J=6.1 Hz, 2H), 3.03 (br. s., 2H), 2.78 (s, 2H), 1.76 (m, 4H), 1.60 (s, 9H).
Reaction SMILES: C(OC1N=NC(C#CC2C=CC=CC=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42](Cl)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:54]([C:56]1[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=1)#[CH:55]>>[CH2:31]([O:38][C:39]1[N:40]=[N:41][C:42]([C:55]#[C:54][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:43][C:44]=1[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C#Cc1cc(F)cc(F)c1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)c1ccccc1
Product: Fc1cc(F)cc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(phenylethynyl)pyridazine (Intermediate 2) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-ethynyl-3,5-difluorobenzene.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].N1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.CCOC(C)=O>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:16]([C:17]1[CH:2]=[C:3]([CH3:4])[C:7]([O:13][CH3:14])=[C:19]([CH3:20])[CH:18]=1)=[N:1]2
Reactant: c1ccncc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OC)c(C)c3)nc2c1
Reaction time: 16 h
Yield: 158.8 %

Procedure:
To a mixture of 2-amino-4,6-dimethoxybenzamide (0.0990 g, 0.555 mmol) and pyridine (44.9 μL, 0.555 mmol) in THF (2.02 mL) was added dropwise a solution of the acid chloride (crude residue described above) in THF (925 μL). After 16 h, the mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (3×75 mL), saturated aqueous NaHCO3 (3×75 mL), and brine (75 mL). The insoluble yellow solid was isolated by filtration to provide the amide (0.150 g, 83%). A mixture of the amide (0.148 g, 0.413 mmol) and 2 M NaOH (7.00 mL) was heated at 85° C. for 19 h, cooled to 5° C., and neutralized with 4 M HCl in dioxanes. The white solid was filtered and rinsed with acetone to provide 5,7-dimethoxy-2-(4-methoxy-3,5-dimethylphenyl)quinazolin-4(3H)-one (0.144 g, 100%). Selected data: 1H NMR (300 MHz, CDCl3) δ 11.00 (s, 1H), 7.90 (s, 2H), 6.74 (d, J=2.33 Hz, 1H), 6.51 (d, J=2.32 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.72 (s, 3H), 2.29 (s, 6H); MS (APCI) m/z 341 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[N:18][NH:19][C:13]=3[C:12]3[CH:20]=[CH:21][CH:22]=[N:23][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[CH2:16][CH2:15][C:14]3[CH:17]=[N:18][NH:19][C:13]=3[C:12]3[CH:20]=[CH:21][CH:22]=[N:23][C:11]2=3)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cn[nH]c2-c2cccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cn[nH]c3-c3cccnc32)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 64.6 %

Procedure:
To a slurry of 0.170 g of 1,4,5,6-tetrahydro-6-(4-nitrobenzoyl)pyrazolo[3,4-d]pyrido[2,3-b]azepine in 8 ml of ethanol under argon is added 0.573 g of stannous chloride dihydrate (SnCl2.2H2O). The mixture is refluxed for 1 hour, diluted with ice-water and made basic with 10% NaHCO3 solution. The mixture is stirred 3.5 hours and extracted with chloroform (3 times). The extract is dried (MgSO4) and the solvent removed under vacuum. Chromatography on silica gel with ethyl acetate as eluent gives 0.10 g of off-white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:28])[N:8]([CH:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5]=2[NH:4][N:3]=1.CCCCCC.C(O)C.C(NCC)C>>[NH2:1][C:2]1[C:6]2[C:7](=[O:28])[N:8]([C@H:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[CH:13][N:12]=3)[C:5]=2[NH:4][N:3]=1
Reactant: CC(C)C(C)n1cc(-c2ccc(N3CCOCC3)cn2)c2[nH]nc(N)c2c1=O
Solvent: CCNCC
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)[C@H](C)n1cc(-c2ccc(N3CCOCC3)cn2)c2[nH]nc(N)c2c1=O
Yield: 44.4 %

Procedure:
Racemic 3-amino-5-(3-methylbutan-2-yl)-7-(5-(morpholin-4-yl)pyridin-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Example 116 (90 mg) was resolved by HPLC (column: CHIRALCEL OJ, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol/diethylamine=700/300/1(v/v/v)) to give the title compound (40 mg) having a longer retention time. 99.2% ee (HPLC (column: CHIRALCEL OJ3, 4.6 mmID×250 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol/diethylamine=700/300/1(v/v/v), flow rate: 1.0 mL/min, retention time: 16.41 min))
Reaction SMILES: [K].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].Cl[CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C=O)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: CCOC(=O)C(C)Cl
Reactant: CC(=O)c1ccc(O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(C)=O)cc1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a solution of the potassium salt of 4-hydroxyacetophenone (25.0 g, 0.14 mol) in DMF (100 mL) is added ethyl 2-chloropropanoate (27.3 g, 0.20 mol) over 30 minutes and stirred at 85°-90° C. for 3 hours under nitrogen. The reaction is filtered to remove KCl and the filtrate is concentrated under reduced pressure to remove DMF and the product is analyzed by GLC. The product is dissolved in ethyl acetate (300 mL) and extracted with 2N NaOH (2×100 mL) and water (100 mL). The organic phase is dried and concentrated to give pure ethyl 2-(4-acetylphenoxy)propanoate (30 g) (yield 75%); m.p. 49.6° C.; IR (KBr) 1747.7 (vs), 1669.8 (vs); 1H NMR (CDCl3) delta 1.18 (t, J=7.2 Hz, 3H), 1.58 (d, J=6.8 Hz, 3H), 2.46 (s, 3H), 4.15 (q, J=7.2, 2H), 4.77 (q, J=32 6.8, 1H), 6.83 and 7.84 (dd, J=9.0 Hz, 4H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, white solid (67 mg, 82%), MS (ISP) m/z=329.4 [(M+H)+], mp 209.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)[CH3:2].[F-].[K+].[N+:15]([C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1Br)([O-:17])=[O:16].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([N+:24]([O-:26])=[O:25])=[CH:23][C:18]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(Br)c([N+](=O)[O-])c1
Reactant: CCOc1ccccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccccc1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 82.4 %

Procedure:
A pressure flask was charged with 2-ethoxyphenylboronic acid (0.66 g, 4.0 mmol), KF (0.77 g, 13 mmol), Pd2(dba)3 (16 mg, 0.02 mmol), and 2,4-dinitro-bromobenzene (0.99 g, 4.0 mmol) in THF (5 mL). The vessel was purged with argon for 1 min followed by the addition of tri-tert-butylphosphine (0.15 ml, 0.48 mmol, 10% solution in hexanes). The reaction vessel was purged with argon for additional 1 min., sealed and heated at 80° C. overnight. After cooling to room temperature, the solution was filtered through a plug of Celite. The filter cake was rinsed with CH2Cl2 (10 mL), and the combined organic extracts were concentrated under reduced pressure to provide the crude product 2′-ethoxy-2,4-dinitro-biphenyl (0.95 g, 82%). No further purification was performed. 1H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.43 (d, J=8.7 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.44 (q, J=6.6 Hz, 2H), 1.24 (t, J=6.6 Hz, 3H); HPLC ret. time 3.14 min, 10-100% CH3CN, 5 min gradient.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1B(O)O>>[OH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[OH:21])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(O)c(B(O)O)c1
Reactant: Cc1ccc(-c2cccc(-c3cccc(Br)n3)n2)c(O)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4ccc(C)cc4O)n3)n2)c1
Yield: 28 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-4-methylphenyl)-2,2′-bipyridine and 2-hydroxy-5-methoxyphenylboronic acid in 28% yield using method F; δH [2H6]-DMSO 13.70,(1H, b), 12.57,(1H, b), 8.38,(1H, d), 8.31,(1H, 8,25-8.17,(2H, m), 8.12,(1H, d), 8.02,(1H, d), 7.65,(1H, d), 7.00,(1H, dd), 6.94,(1H, d), 6.82,(2H, m), 3.82,(3H, s), 2.33,(3H, s); MS 385 (MH)+; HPLC retention time (system 1) 4.28 minutes.
Reaction SMILES: [Na].[CH:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=2[Cl:19])=[C:6]([CH2:8][C:9]([O-:11])=[O:10])[CH:7]=1.[Na+]>>[CH:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [Na]
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
sodium (chemical name 2-[(2.6-dichlorophenyl)amino]benzeneacetic acid sodium salt) is an effective and widely used non-steroid anti-inflammatory agent marketed as Voltaren® (Ciba Geigy) in several countries.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:5](O)=[O:6].C([N:20](CC)CC)C.ClC(OCC(C)C)=O.N>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)[C:5]([NH2:20])=[O:6]
Reactant: CCN(CC)CC
Reactant: CN1CCN(c2ccc(C(=O)O)cc2F)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2ccc(C(N)=O)cc2F)CC1
Reaction time: 3 h
Yield: 12 %

Procedure:
To 3-fluoro-4-(4-methylpiperazin-1-yl)benzoic acid (250 mg, 1.05 mmol) in THF (10 ml) was added triethylamine (221 μl, 1.58 mmol) and isobutyl chloroformate (145 μl, 1.10 mmol). The mixture was stirred at 0° C. for 1 hour, at which time concentrated aqueous ammonia (3 ml) was added. The reaction mixture was stirred for 3 hours then the volume was reduced in vacuo. The residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated to afford (30.0 mg, 12%) of 3-fluoro-4-(4-methylpiperazin-1-yl)benzamide, which was used without further purification. MS (EI) for C12H16FN3O: 238 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:14][C:11]1[O:10][C:9]([C:4]2[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=2)=[CH:13][CH:12]=1
Reactant: Clc1cc(-c2ccco2)nc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(-c2ccc(Br)o2)nc(Cl)n1
Yield: 65.4 %

Procedure:
To a stirred solution of 2,4-Dichloro-6-furan-2-yl-pyrimidine (1.44 g, 6.71 mmol) in DMF (20 ml) was added N-bromosuccinimide (1.31 g, 7.38 mmol) in a portionwise fashion. The resultant mixture was stirred at room temperature for a 2.5 hours before being diluted in EtOAc (50 ml) and washed with water (2×50 ml). The organic extract was dried (MgSO4), filtered and concentrated in vacuo to give an orange, semi-crystalline slurry. The crude residue was washed with ether and filtered to leave the desired product (1.29 g, 99%) as a whited crystalline solid in suitably clean form to be used without any further purification. m/z (LC-MSW, ESP):294 [M+H]+, R/T=5.09 mins.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1([CH3:30])[CH:26]2[CH2:27][CH:22]1[CH2:23][CH:24]=[C:25]2[CH2:28]O.C(Cl)(Cl)(Cl)[Cl:32]>>[Cl:32][CH2:28][C:25]1[CH:26]2[CH2:27][CH:22]([CH2:23][CH:24]=1)[C:21]2([CH3:30])[CH3:20]
Reactant: CC1(C)C2CC=C(CO)C1C2
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)C2CC=C(CCl)C1C2

Procedure:
A mixture of triphenylphosphine (7.87 g, 0.03 mol) and 6,6-dimethylbicyclo[3.1.1]hept-2-ene-2-methanol (3.04 g, 0.02 mol) in dry carbon tetrachloride (14.0 ml) was stirred and heated at 60° for 4.0 h. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford a semi crystalline mass. This residue was triturated with n-pentane (30 ml), and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the resulting oil was distilled, to afford 2-chloromethyl-6,6-dimethylbicyclo[3.1.1]hept-2-ene as a colourless oil, b.p. 32°-33°/0.2 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]([F:19])[F:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:50]([O:52][C:53]([N:55]1[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1)=[O:54])[CH3:51]>C(OCC)(=O)C>[CH2:50]([O:52][C:53]([N:55]1[CH2:56][CH2:57][N:58]([C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][CH:17]([F:19])[F:18])[CH2:59][CH2:60]1)=[O:54])[CH3:51]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(N[C@@H](CC(F)F)C(=O)O)OCc1ccccc1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(F)F)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 114 mg (S)-2-Benzyloxycarbonylamino-4,4-difluoro-butyric acid were added 0.11 ml N-ethylmorpholine, 138 mg TOTU and 66 mg 1-ethoxycarbonylpiperazine. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 168 mg
Reaction SMILES: [NH:1]([C@@H:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][OH:5])N>CO.[Ni]>[NH2:1][C@@H:3]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:4][OH:5]
Reactant: NN[C@H](CO)CC1CCCOC1
Agent: [Ni]
Solvent: CO
Product: N[C@H](CO)CC1CCCOC1
Yield: 102.8 %

Procedure:
To the solution of (2S)-2-hydrazinyl-3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (5.79 g, 0.033 mol) in MeOH (100 mL) was added Raney Ni. The flask was degassed and equipped with a hydrogen-inflated balloon. The flask was dipped into an ultrasound bath filled with water and sonicated for 4 hr at rt until the starting material was completely consumed. The mixture was then filtered through celite, and the filter cake was washed with MeOH (2×30 mL). Removal under reduced pressure gave (2S)-2-amino-3-(tetrahydro-2H-pyran-3-yl)propan-1-ol (5.4 g, 90%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].Cl.[NH2:37][CH2:38][CH2:39][N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42].C[O-].[Na+]>CCO>[CH3:44][S:41]([N:40]([CH3:45])[CH2:39][CH2:38][NH:37][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[CH:8]2)=[O:4])(=[O:43])=[O:42]
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CN(CCN)S(C)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O)S(C)(=O)=O
Temperature: 140 °C
Yield: 53.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (38.5 mg, 0.083 mmol), N-(2-amino-ethyl)-N-methyl-methanesulfonamide HCl salt (78 mg, 0.42 mmol), and NaOMe (22 mg, 0.42 mmol) in EtOH (3 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 26 mg of the title compound. MS: (+) m/z 584.26 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:35]([O:38][C:39](Cl)=[O:40])([CH3:37])[CH3:36]>C(Cl)Cl>[CH:35]([O:38][C:39](=[O:40])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:26][CH2:27][CH2:28]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:11]=3)=[CH:4][CH:3]=1)([CH3:37])[CH3:36]
Reactant: N#Cc1c(-c2ccc(N)cc2)n(C2CCC2)c2cc(N3CCOCC3)ccc12
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(N4CCOCC4)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
A solution of 2-(4-amino-phenyl)-1-cyclobutyl-6-morpholin-4-yl-1H-indole-3-carbonitrile (0.112 g, 0.3 mmol), pyridine (1.0 mL) in CH2Cl2 (2.0 mL) was treated with isopropylchloroformate (1.0 M in toluene, 0.6 mL, 0.6 mmol). The mixture was stirred at room temperature for 5 h and diluted with CH2Cl2 (5 mL). The organic layer was separated, washed with HCl (1.0 N, 3×2 mL), water (5 mL×2) and brine (5 mL), and purified on silica gel (CH2Cl2/EtOAc, 9:1) to provide [4-(3-cyano-1-cyclobutyl-6-morpholin-4-yl-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (0.12 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:5][C@H:6]([NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH2:27][C:26]2=[O:32])=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.CCCCCC(COC(C1C=CN=CC=1)=O)C.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:5][C@H:6]([NH:20][C:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][CH2:27][CH:26]2[OH:32])=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3c(c2)C(=O)CC3)c1
Agent: CCCCCC(C)COC(=O)c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc3c(c2)C(O)CC3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ice-cold solution of N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-oxoindane-5-carboxamide prepared by the method in EXAMPLE SP-201 (66 mg, 0.13 mmol) in methanol (3 mL) is added sodium borohydride (20 mg, 0.52 mmol). The reaction stirred at room temperature 3 h. The reaction is concentrated under reduced pressure, redissolved in water (3 mL) and partitioned into ethyl acetate. The organic layer is washed with water, saturated sodium bicarbonate, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 495.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1>C(O)(=O)C>[CH3:19][C:17]1[NH:16][N:15]=[C:14]([NH:13][C:1]2[NH:2][C:6](=[O:7])[C:5]3[C:4]([CH:3]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:18]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: N#CCc1ccccc1C(=O)O
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3ccccc3c(=O)[nH]2)n[nH]1
Temperature: 130 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
2-Cyanomethyl-benzoic acid (1.61 g, 0.01 mol), 3-amino-5-methylpyrazol (1 g, 0.01 mol) and acetic acid (15 ml) were sealed in a bottle. The mixture was heated at 130° C. for 20 minutes under microwave irradiation. The mixture was concentrated, and the residue was dissolved in 5 ml methanol (MeOH). The resulting solution was added dropwise to 200 ml water. After stirred for 1 hour, the solid was collected, and dried to give product (1.8 g, 75% yield). LC-MS: 241 (MH+)