Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C@:11]1([CH3:20])[CH2:16][S:15](=[O:18])(=[O:17])[CH2:14][C:13]([NH2:19])=[N:12]1.C(N(CC)CC)C>C(O)C.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:11]2([CH3:20])[CH2:16][S:15](=[O:17])(=[O:18])[CH2:14][C:13]([NH2:19])=[N:12]2)[CH:4]=1
Reactant: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CS(=O)(=O)CC(N)=N1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@]1(c2cc(N)ccc2F)CS(=O)(=O)CC(N)=N1
Yield: 87.6 %

Procedure:
A solution of (R)-5-(2-fluoro-5-nitro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (584 mg, 1.94 mmol, Eq: 1.00) in ethanol (45 ml), triethylamine (196 mg, 270 μl, 1.94 mmol, Eq: 1.00) and Pd/C (206 mg, 194 μmol, Eq: 0.1) was hydrogenated at room temperature for 1 hour. Filtered off the catalyst, washed with ethanol, evaporated the filtrate and dried in HV to give the (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (460 mg, 1.7 mmol, 87.5% yield) as a an off-white foam. MS (ISP): m/z=272.4 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.[Cl:34][C:35]1[CH:36]=[C:37]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:38]=[C:39]([Cl:45])[C:40]=1[O:41][CH2:42][CH2:43][NH2:44]>ClCCl>[Cl:34][C:35]1[CH:36]=[C:37]([O:46][CH2:47][CH:48]=[C:49]([Cl:51])[Cl:50])[CH:38]=[C:39]([Cl:45])[C:40]=1[O:41][CH2:42][CH2:43][NH:44][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=1
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 62.6 %

Procedure:
To a solution of 0.15 g of 4-trifluoromethylcinnamic acid and 0.07 g of triethylamine dissolved in 5 ml of dichloromethane was added 0.14 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride, while stirring under ice cooling. After stirring for 30 minutes, a solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene dissolved in 5 ml of dichloromethane was added dropwise. After stirring at room temperature for 12 hours, the reaction mixture was concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.20 g of 3,5-dichloro-4-(2-(4-trifluoromethylcinnarnamido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (63% yield), m.p., 109.4° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:13][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: ClCc1ccc(Cl)nc1
Solvent: CC#N
Product: CCCNCc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 100.8 %

Procedure:
In 15 ml of acetonitrile was dissolved 6.05 g (0.0373 mole) of 6-chloro-3-pyridylmethyl chloride, and under cooling with ice-water and stirring, the solution was added dropwise to a solution of 10.97 g of n-propylamine in 50 ml of acetonitrile. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour and at an external temperature of 50° C. for an additional 1 hour. The acetonitrile was distilled off and the residue was diluted with aqueous sodium hydrogen carbonate solution and extracted with CH2Cl2 (100 ml×3). The extract was dried over MgSO4 and distilled to remove CH2Cl2, whereby 6.94 g of N-(6-chloro-3-pyridylmethyl)-N-n-propylamine was obtained as a yellow-brown oil.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[C:6]=1[CH2:20][C:21]([OH:23])=O)([O-])=O>C(O)C.[Pd]>[ClH:1].[CH2:14]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:12][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH2:20][C:21](=[O:23])[NH:2]2)[CH2:15][CH3:16]
Reactant: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1CC(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCN(CCC)CCc1cccc2c1CC(=O)N2
Reaction time: 5.5 h
Yield: 77.5 %

Procedure:
A mixture of 5.83 g (16.9 mmoles) of 2-nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride and 0.6 g of 5% palladium-on-carbon in 250 cc of ethanol was hydrogenated at moderate pressure over 5.5 hours. The catalyst was filtered, washed with ethanol, and the filtrate evaporated to dryness in vacuo. The white residue was crystallized from 550 cc of hot acetonitrile to give 3.89 g of 4-(2-di-n-propylaminoethyl)-2(3H)-indolone hydrochloride, mp 240°-2°.
Reaction SMILES: C[SiH](O)C.C[Si](C)(C)C.C[Si](O)(C)C.[CH2:15]([N:22]=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N)C(C)C>C1([SiH3])C=CC=CC=1.N1CCCCC1.CO.C1COCC1>[CH2:15]([NH:22][CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(CN=C2CCc3ccccc32)cc1
Agent: C[SiH](C)O
Agent: C[Si](C)(C)O
Agent: [SiH3]c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: C[Si](C)(C)C
Product: c1ccc(CNC2CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.29 h
Yield: 101.3 %

Procedure:
Typical experimental procedure: A dry resealable Schlenk flask under argon was charged with (S,S-(EBTHI) TiF2 (9 mg, 0.025 mmol) and 1 mL of dry THF. The resulting yellow solution was heated to 60 C. and PhSiH3 (12 μL, 0.1 mmol), piperidine (9 μL, 0.1 mmol) and methanol (4 μL, 0.1 mmol) were added via syringe. The mixture was stirred at 60 C. for 15-20 min, resulting in a color change from yellow to green. At this point, THF (1 mL) and PMHS (1.65 mL, 27 mmol) were added via syringe. The sealed Schlenk flask was then removed from the oil bath, cooled to room temperature, and brought into an argon filled glovebox. N-Benzyl-1-indanimine (0.64 g, 2.7 mmol) was added, and the reaction mixture was heated to 65 C. and the color of the reaction mixture changed to brown. To this solution, isobutylamine (0.6 mL, 6 mmol) was added during a period of 2.5 h (0.25 mL/h flow rate) using a syringe pump. When the amine addition was finished, the color of the reaction mixture had changed from brown to green, and analysis by GC showed complete consumption of the starting material. The reaction mixture was cooled to room temperature, removed from the glovebox, diluted with Et2O (30 mL) and stirred with 1 M HCI (15 mL) for 0.5 h (caution: vigorous bubbling). The aqueous layer was separated, made basic with 3 M NaOH and extracted with ether. The combined ether layers were dried (MgSO4) and concentrated in vacuo to afford 611 mg of (+)-N-benzylindan-1-amine (95% yield, 92% ee). Note: The amine promoter could be added portionwise, by syringe, in the case of more reactive substrates or when using a higher catalyst loading. For reactions using b 1 mol % catalyst, amine addition was performed in a hood under argon in a septum-capped Schlenk flask.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][N:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]([Cl:17])[N:9]=1)C.Cl>C(O)C>[CH2:18]([N:7]1[CH2:6][CH2:5][C:4](=[O:3])[NH:14][C:13]2[CH:12]=[N:11][C:10]([Cl:17])=[N:9][C:8]1=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: O=C1CCN(Cc2ccccc2)c2nc(Cl)ncc2N1
Yield: 18.5 %

Procedure:
To a solution of 1.1 g (0.003 mole) of 3-[benzyl-(2-chloro-5-nitro-pyrimidin-4-yl)-amino]-propanoic acid ethyl ester (IV-22) in 20 mL of ethanol was added 1.7 g (0.0075 mole) of stannous chloride dehydrate and 0.5 mL of hydrochloric acid. The mixture was heated at 60 degrees for 2 hrs. The solvent was evaporated under reduced pressure. The residue was taken up in 50 mL of water and extracted three times with 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (100:0-95:5) gave 0.16 g of 9-benzyl-2-chloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-22) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:5][CH:4]=1.[BrH:14]>>[BrH:14].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCN)cc1
Agent: Br
Product: NCCCCc1ccc(O)cc1
Yield: 90 %

Procedure:
Amine 3 (2.32 g, 0.012 mol) was stirred in boiling 48% HBr (50 mL) for 3 h. After the reaction was completed, argon was bubbled through the solution and the solvent was evaporated under reduced pressure. The solid residue was dried above KOH to provide 3.1 g (90%) of 4. APCI MS m/z=166[C10H15NO+H]+
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]3[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:44]=3[N:45]=2)=[CH:37][CH:36]=1)[CH:10]1[CH2:19][CH2:18][CH2:17][C:16]2[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]1=2)=O)(C)(C)C>O1CCOCC1>[ClH:1].[ClH:1].[CH3:50][C:47]1[CH:48]=[CH:49][C:43]2[O:42][C:41]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][O:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH2:26][CH2:25][NH:9][CH:10]4[CH2:19][CH2:18][CH2:17][C:16]5[N:15]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=[CH:12][C:11]4=5)=[CH:40][CH:39]=3)=[N:45][C:44]=2[CH:46]=1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccccc1OCc1ccc(-c2nc3cc(C)ccc3o2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(-c2nc3cc(C)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5 ml of a 4 N solution of hydrogen chloride in dioxane were added to 581 mg (0.88 mmol) of (+)-ethyl 5-{(tert-butoxycarbonyl)[2-(2-{[4-(5-methyl-1,3-benzoxazol-2-yl)benzyl]oxy}-phenyl)-ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Example 25A), and the mixture was stirred at room temperature for 4 h. The reaction solution was then concentrated to dryness and the residue was dried under high vacuum overnight. This gave 564 mg (0.88 mmol, 100% of theory) of the target product as a beige solid.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6](C)[C:5]=1[NH:11][S:12](C1C=CC(OC)=CC=1)(=[O:14])=[O:13].Cl.[N:25]1C=CC(CCl)=CC=1>>[N:25]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:5][NH:11][SH:12](=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1ccncc1
Agent: Cl
Product: O=[SH](=O)NCc1ccccn1
Yield: 94 %

Procedure:
Following the procedure of Example 45, 0.750 g (2.239 mmol) of the product of Example 3 was alkylated with 4-picolyl chloride hydrochloride to give 0.897 g (94%) of the N-picolyl sulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].CC(C)([O-])C.[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: COC(=O)CCn1ccc2cc([N+](=O)[O-])ccc21
Yield: 65.3 %

Procedure:
Reaction of 5-nitro indole (3.0 g) with methyl acrylate (2.29 g) in the presence of potassium t-butoxide (0.258 g) and tetrabutylammonium bromide according to the method of Preparation 19 gave the title compound (3.0 g),m.p. 97°-99° C. Found: C,57.86; H,4.84; N,10.78. C12 H12N2O4 requires: C,58.06; H,4.87; N,11.28%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:52][C:53]1(C)C(C)(C)OB(C=C)O1>CCO.O.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:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:52]=[CH2:53])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: O
Product: C=Cc1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)c(-n2ccc(C)n2)c1
Temperature: 80 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.388 mmol, see Example 1u) in EtOH:H2O (15 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (90 mg, 0.58 mmol), KHCO3 (389 mg, 3.88 mmol), and PdCl2(PPh3)2 (41 mg, 0.058 mmol). The reaction mixture was heated to 80° C. for 1 h, then cooled to RT. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification with a 40 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.OS(O)(=O)=O>>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:13])[C:11](=[O:12])[C:2]1=[O:1]
Reactant: Oc1nc2ccccc2c(O)c1O
Agent: O=S(=O)(O)O
Product: O=C1Nc2ccccc2C(=O)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.1 %

Procedure:
To a mixture of 335 mg (1.89 mmol) of 11a in 4 mL of aqueous 0.1N H2SO4 was added dropwise 10 mL of aqueous 0.2M KIO4 (2 mmol) at 25° C. The mixture was stirred at 25° C. for 2 h, filtered and washed with water, dried to leave 222 mg (67%) of 12a as an almost colorless solid, mp>250° C. 1H NMR (DMSO-d6), 7.043 (d, 1, J=8.4), 7.089 (t, 1, J=7.8), 7.232 (s, 2), 7.577 (t, 1, J=7.8), 7.735 (d, 1, J=7.5), 10.735 (s, 1). 1H NMR (DMSO-d6 +D2O), 7.043 (d, 1), 7.098 (t, 1), 7.577 (t, 1), 7.735 (d, 1). MS, 175 (20, M+), 147 (20), 119 (100), 92 (60). High resolution MS, Calcd for C9H5NO3 175.0267, found 175.0275.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cc(-c2cccc(OC(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Yield: 95 %

Procedure:
Starting from 1.9 g (4.63 mmol) of ethyl 1-(3-chlorophenyl)-5-[3-(trifluoromethoxy)phenyl]-1H-pyrazole-3-carboxylate from example 6A and 2.59 g (46.25 mmol) of potassium hydroxide, 1.68 g (4.4 mmol, 95% yield of theory) are obtained as crystals according to the method described in example 7A.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][N:27]3C(=O)C4=CC=CC=C4C3=O)[CH2:18][CH2:17]2)[CH2:6]1.NN.OS(O)(=O)=O>C(O)C>[Cl:1][C:2]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:3]=1[CH2:4][N:5]1[CH2:9][C@H:8]([C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[C@@H:7]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:18][CH2:17]2)[CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1
Agent: NN
Agent: O=S(=O)(O)O
Solvent: CCO
Product: NCCCOCC1CCN(C[C@H]2CN(Cc3ccc(Cl)cc3Cl)C[C@@H]2c2ccsc2)CC1

Procedure:
A solution of 0.2 g (0.32 mmol) of 1-(2,4-dichlorobenzyl)-3-(S)-(4-(3-phthalimidopropyloxymethyl)piperidinylmethyl)-4-(S)-(3-thienyl)pyrrolidine (Example 20) and 0.2 mL (6.4 mmol) of hydrazine in 2 mL of ethanol was heated at 60° C. for 5 h. To the reaction mixture was added 20 mL of 10% H2SO4 and the mixture was extracted three times with ethyl acetate. The aqueous layer was brought to pH=12 by addition of 15% NaOH and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and the filtrate was concentrated to give the title compound. Mass Spectrum (ESI) m/e=496 (M+1 35Cl, 35Cl), 498 (M+1 35Cl, 37Cl), and 500 (M+1 37Cl, 37Cl). [α]D=+14.9 (c=0.875, CHCl3).
Reaction SMILES: BrC1C=C(N[C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=CC=1.NC1C=C(OC)C(OC)=CC=1C(OC)=[O:27].C(N)=O>O>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[NH:12][C:11](=[O:27])[N:10]=[CH:9]2
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1OC
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Solvent: NC=O
Solvent: O
Product: COc1cc2cnc(=O)[nH]c2cc1OC

Procedure:
In an example, A1 was prepared essentially as described in Barker, AJ. European Patent Application 0 566 226 A1, Oct. 20, 1993; and Gazit et al., Bioorg. Med. Chem. 4:1203-1207, 1996. Briefly, methyl 2-amino-4,5-dimethoxybenzoate was treated with formamide at 180° C. The reaction was cooled and diluted with water. The precipitate was collected by filtration, washed with water and dried to give 6,7-dimethoxyquinazolone, which was treated with thionyl chloride and dimethylformamide at reflux, concentrated, and stirred with sodium bicarbonate solution. The resulting solid was collected and crystallized from hexane to give 4-chloro-6,7-dimethoxyquinazoline, which was refluxed with 3-bromoaniline in ethanol, cooled, treated with 1 normal NaOH and the resulting solid collected by filtration to yield 4-(3-bromophenylamino)-6,7-dimethoxyquinazoline (A1).
Reaction SMILES: C(NC(C)C)(C)C.FC1C(I)=CC(C)=CN=1.FC1C(I)=C([Li])C(C)=CN=1.[F:27][C:28]1[C:33]([Li])=[C:32]([I:35])[C:31]([CH3:36])=[CH:30][N:29]=1.[CH3:37][O:38][C:39]1[C:46]([O:47][CH3:48])=[C:45]([O:49][CH3:50])[CH:44]=[C:43]([CH3:51])[C:40]=1[CH:41]=[O:42]>O1CCCC1.O.CCCCCC>[CH3:37][O:38][C:39]1[C:46]([O:47][CH3:48])=[C:45]([O:49][CH3:50])[CH:44]=[C:43]([CH3:51])[C:40]=1[CH:41]([C:33]1[C:28]([F:27])=[N:29][CH:30]=[C:31]([CH3:36])[C:32]=1[I:35])[OH:42]
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Reactant: [Li]c1c(F)ncc(C)c1I
Agent: Cc1cnc(F)c(I)c1
Agent: [Li]c1c(C)cnc(F)c1I
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(C(O)c2c(F)ncc(C)c2I)c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
8.90 ml (1.57 mol/l hexane solution) was dropwise added at −78° C. to a solution having 1.34 g (13.3 mmol) of diisopropylamine dissolved in 27 ml of tetrahydrofuran, followed by stirring for 30 minutes. To this solution, a solution having 3.15 g (13.3 mmol) of 2-fluoro-3-iodo-5-methylpyridine obtained in Step (a) dissolved in 5 ml of tetrahydrofuran was added, followed by stirring for 1 hour, so that 2-fluoro-3-iodo-5-methyl-4-pyridyllithium formed at the initial stage was isomerized to 2-fluoro-4-iodo-5-methyl-3-pyridyllithium. To the reaction mixture, a solution having 2.79 g (13.3 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 5 ml of tetrahydrofuran was added, followed by stirring for 2 hours. After the temperature was increased to room temperature, 50 ml of water was added, followed by extraction with ethyl ether. The organic layer was dried over magnesium sulfate and subjected to filtration, the solvent was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography to obtain 4.45 g (yield: 75%) of (2,3,4-trimethoxy-6-methylphenyl)(2-fluoro-4-iodo-5-methyl-3-pyridyl)methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C:7](=[O:12])[CH2:6][CH2:5]2.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH:7]([OH:12])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)c(F)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCc2cc(F)c(F)cc21
Reaction time: 48 h
Yield: 99.6 %

Procedure:
5,6-Difluoroindan-1-one (59.3 g, 0.353 mol) was dissolved in 1 L of ethanol and sodium borohydride (6.68 g, 0.176 mol) was added. The mixture was stirred for 48 hours and the ethanol was removed by evaporation under reduced pressure. The residue was partitioned between diethyl ether and water and the mixture was acidified with 1N hydrochloric acid. The mixture was dried over magnesium sulfate and filtered. The solvents were evaporated giving 5,6-difluoro-1-hydroxyindane (59.8 g) as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:31]3[CH2:34][N:33]([C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)[CH2:32]3)=[O:30])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.[CH:41]1([CH:44]=O)[CH2:43][CH2:42]1.C(O)(=O)C.C([BH3-])#N>CO>[CH:41]1([CH2:44][N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([CH:31]4[CH2:34][N:33]([C:35]5[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=5)[CH2:32]4)=[O:30])=[CH:26][CH:27]=3)[CH2:17][CH2:16]2)[CH2:43][CH2:42]1
Reactant: O=CC1CC1
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)C1CN(c2cccnc2)C1
Agent: [BH3-]C#N
Solvent: CO
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(OC2CCN(CC3CC3)CC2)cc1)C1CN(c2cccnc2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
In a 20 mL vial was added N-(4-(piperidin-4-yloxy)phenyl)-1-(pyridin-3-yl)azetidine-3-carboxamide bis(2,2,2-trifluoroacetate) (67 mg, 0.12 mmol) dissolved in methanol (2.0 mL) followed by the addition of cyclopropanecarbaldehyde (10 mg, 0.14 mmol) dissolved in methanol (0.45 mL), followed by the addition of neat acetic acid (66 μL, 1.2 mmol). The mixture was shaken for 1 hour at 70° C. After that, 265 mg of MP-cyanoborohydride resin (2-3 mmol/g) was added and the resulting mixture was shaken at 70° C. overnight. The reaction mixture was filtered, checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 DMSO/CH3OH and purified by reverse phase HPLC. 1H NMR (500 MHz, pyridine-d5/D2O) δ ppm 8.20-8.25 (m, 1 H) 8.13 (d, J=2.75 Hz, 1 H) 7.98-8.03 (m, 2 H) 7.11 (dd, J=8.24, 4.58 Hz, 1 H) 7.02-7.07 (m, 2 H) 6.72-6.78 (m, 1 H) 4.58 (d, J=2.75 Hz, 1H) 4.34 (t, J=6.71 Hz, 2 H) 4.05 (t, J=7.63 Hz, 2 H) 3.80-3.92 (m, 1 H) 3.34 (s, 4 H) 2.92 (d, J=7.32 Hz, 2 H) 2.32-2.44 (m, 2 H) 2.12 (s, 2 H) 1.09-1.22 (m, 1 H) 0.51-0.58 (m, 2 H) 0.28-0.34 (m, 2 H); MS (ESI(+)) m/e 407 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16].C(N(CC)CC)C.O>C(OC(O)C)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH:15]([OH:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCC(O)c1ccccc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: CCOC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: OC(CNc1ccnc2cc(Cl)ccc12)c1ccccc1

Procedure:
A solution of 4,7-dichloroquinoline (19.8 g), 2-amino-1-phenylethanol (13.7 g) and 20 ml of triethylamine (14.5 g) in 10 ml of ethoxyethanol was heated at 130° C. overnight. The mixture was poured into 600 ml of water and the solid product was collected by filtration, recrystallized from ethoxyethanol and washed with ethanol. The yield was 16 g, mp 221°-222° C.