Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[Cl:16][C:17]1[CH:30]=[CH:29][C:20]2[S:21][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:24])[C:19]=2[CH:18]=1>N1C=CC=CC=1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:25]([C:22]3[S:21][C:20]4[CH:29]=[CH:30][C:17]([Cl:16])=[CH:18][C:19]=4[C:23]=3[CH3:24])(=[O:27])=[O:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: Cc1c(S(=O)(=O)Nc2ccc3[nH]cc(CCN(C)C)c3c2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.8 %

Procedure:
To a solution of 3.05 g (15 mMol) of 5-amino-3-(2-dimethylaminoethyl)-1H-indol in 100 ml of pyridine is added dropwise at ambient temperature a solution of 4.21 g (15 mMol) of 5-chloro-3-methyl-benzo[b]thiophene-2-sulphonyl chloride in 20 ml of pyridine. The reaction mixture is stirred at ambient temperature for 20 hours. It is then evaporated to dryness, slightly alkalinised with diluted ammonia and dissolved in ethyl acetate. The organic phase is washed with water and a saturated solution of sodium bicarbonate, it is separated and dried with anhydrous sodium sulphate. The organic solution is evaporated to dryness and the resulting solid is repeatedly washed with ethyl ether, to yield 5.5 g (82%) of N-[3-(2-dimethylaminoethyl)-1H-indol-5-yl]-5-chloro-3-methyl-benzo[b]thiophene-2-sulphonamide as a solid with m.p.=226-227° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[OH:10].Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:7]1[C:2]2[NH:1][C:13](=[O:14])[CH2:12][O:10][C:3]=2[CH:4]=[CH:5][C:6]=1[F:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1c(O)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2ccc(F)c(F)c2N1
Yield: 14.6 %

Procedure:
A crude of 2-amino-3,4-difluorophenol (0.68 g, 4.7 mmol), 2-chloroacetyl chloride (0.58 g, 5.2 mmol) and K2CO3 (1.36 g, 9.9 mmol) were mixed according to GP1. Purified by prep RP-HPLC to give the title compound (0.127 g, 14.5%). Rf=0.63 (heptanes/EtOAc 1:1). 1H NMR (CDCl3) δ 6.69-6.57 (m, 2H), 4.47 (s, 2H); 13C NMR (CDCl3) δ 165.0, 146.2 (dd, J=241.8 Hz, J=10.4 Hz), 140.3 (t, J=2.32 Hz), 138.7 (dd, J=247.2 Hz, J=17.3 Hz), 67.1 (t, J=2.7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:17][N:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)[C:9]2[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=2[C:7]1=[O:27])=[O:5])[CH3:2].BrBr.N#N.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[C:8]2[CH:13]=[N:12][C:11]([S:14][CH3:15])=[N:10][C:9]=2[N:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH2:23][CH2:22][CH2:21]3)[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(c2ccc3c(c2)CCC3)c2nc(SC)ncc2C1=O
Agent: BrBr
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(SC)ncc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
To a solution of 8-indan-5-yl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.32 g, 0.84 mmol) in 5 mL of methylene chloride (CH2Cl2) was added bromine (43 μL, 0.84 mmol) slowly under N2. The solution was stirred at room temperature for 2 hours (or to completion). The solvent was removed under vacuum without heating. The residue was redissolved in 2 mL of CH2Cl2, and was added triethylamine (234 μL, 1.68 mmol) in 1 mL of CH2Cl2. The solution was stirred at rt for 4 hours. The progress of the reaction was monitored by LC-MS. The solvent was evaporated and the residue was applied onto a silica gel column. The product was eluted with EtOAc/hexanes (1:5-1:2.5, v/v) and obtained as a white solid (0.30 g, 94%). 1H NMR (300 MHz, CDCl3) δ (ppm): 9.42 (s, 1H), 8.59 (s, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.24 (s, 1H), 7.16 (d, J=7.8 Hz, 1H), 4.40 (q, 2H), 3.00 (m, 4H), 2.35 (s, 3H), 2.10 (m, 2H), 1.40 (t, 3H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:18]([NH2:22])(=[O:21])[CH:19]=[CH2:20]>O>[S:1]=[C:2]1[N:6]([CH2:20][CH2:19][C:18]([NH2:22])=[O:21])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1
Reactant: C=CC(N)=O
Reactant: Sc1nc2ccccc2s1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)CCn1c(=S)sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
To a stirred solution at 50° C. containing 86 g (0.5 mol) of 2-mercaptobenzothiazole, 60.8 g (0.6 mol) of triethylamine and 500 ml of water, 43 g (0.6 mol) of acrylamide was added in one portion. After stirring at 60°-70° C. for 24 hours, the stirred reaction mixture was cooled to 25° C., the solid collected by filtration, washed with water until neutral and airdried at 50° C. The product, 2-thioxo-3(2H)-benzothiazole-propanamide, mp 226°-227° C. was obtained in 77% yield.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][O:19]C2CCCCO2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCOCC1>[CH2:26]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:13][CH2:14]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](OCCCOC3CCCCO3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: OCCCO[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
trans-N,N-Dibenzyl-4-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]cyclohexanamine (170 ml) was dissolved in methanol (1 mL), and a 4 M solution (972 μL) of hydrogen chloride in 1,4-dioxane was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-{[trans-4-(dibenzylamino)cyclohexyl]oxy}propan-1-ol (110 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C([O:23][P:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C.C(#N)C>CCOC(C)=O>[C:7]1([P:24](=[O:23])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOP(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.083 mmol), Cesium Fluoride (70 mg, 0.461 mmol), Ethoxydiphenylphosphane (78 mg, 0.33 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf: 0.3 (1:3 EtOAc:Pet Ether); White Solid; 17.5 mg, 75%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.74-7.63 (m, 6H), 7.59-7.51 (m, 3H), 7.50-7.40 (m, 6H); 13C NMR (100 MHz, CDCl3, TMS) δ 132.5 (d, J=104.0 Hz), 132.1 (d, J=10.0 Hz), 131.9 (d, J=2.3 Hz); 128.5 (d, J=12.4 Hz); 31P NMR (162 MHz, CDCl3) δ 29.2; Mass (M+Na)+ 301; Known Compound, Lit. K. Prokop, D. Goldberg, J. Am. Chem. Soc. 2012, 134, 8014.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].[F:24][C:25]([F:45])([F:44])[C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:25]([F:45])([F:44])[F:24])[O:33][N:32]=2)=[O:36])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: COc1cc2ncnc(Oc3cc(N)ccc3F)c2cc1OC
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)ccc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline from the previous step (150 mg, 0.476 mmol) and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (179 mg, 0.571 mmol) in anhydrous THF (5 mL), was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture was stirred at rt for 15 h. Concentration in vacuo followed by purification via silica gel column chromatography (eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate), afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (35 mg, 14%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.79 (brs, 1H), 9.01 (s, 1H), 8.58 (s, 1H), 7.70 (m, 1H), 7.58 (s, 1H), 7.30-7.42 (m, 3H), 6.86 (s, 1H), 4.00 (s, 6H), 1.54 (s, 6H); LC-MS (ESI) m/z 536 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][C:21]([CH3:28])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][CH:17]([OH:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH3:28]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1
Product: CC(C)(NC(=O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3-hydroxy-azetidin-1-yl)-pyridine-2-carboxylic acid and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=389.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[N:57]=[CH:58][S:59][C:60]=1[C:61](O)=[O:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:61]([C:60]2[S:59][CH:58]=[N:57][C:56]=2[CH3:55])=[O:62])[CH2:49][CH2:48]1
Reactant: Cc1ncsc1C(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncsc1C(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 62 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 4-methyl-1,3-thiazole-5-carboxylic acid as starting materials in 62% yield. LCMS for C29H30ClN8O2S (M+H)+: m/z=589.2.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]2[N:41]([N:43]=[C:44]([O:46][CH3:47])[N:45]=2)[CH:42]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:38]=[CH:39][C:40]4[N:41]([N:43]=[C:44]([O:46][CH3:47])[N:45]=4)[CH:42]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: COc1nc2ccc(Br)cn2n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: COc1nc2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)cn2n1
Yield: 66 %

Procedure:
The title compound was prepared from (5)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-one and 6-bromo-2-methoxy-[1,2,4]triazolo[1,5-a]pyridine following a procedure analogous to that described in EXAMPLE 7. Yield: 66% of theory; Mass spectrum (ESI+): m/z=501 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.81 (s, 3H), 1.19 (s, 3H), 1.48 (d, J=7.0 Hz, 3H), 2.03 (s, 2H), 2.13-2.22 (m, 1H), 2.38-ca. 2.53 (m, 2H) superimposed on DMSO-d5, 3.00-3.07 (m, 1H), 4.04 (s, 3H), 4.23 (s, 1H), 5.44 (q, J=7.0 Hz, 1H), 6.98 (d, J=8.2 Hz, 2H), 7.27-7.40 (m, 5H), 7.51 (dm, J=8.2 Hz, 2H), 7.67 (d, J=9.2 Hz, 1H), 7.82 (dd, J=9.2, 1.8 Hz, 1H), 9.05 (hardly resolved d, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6](O)[C:7]2[C:8]([N:23]=1)=[N:9][C:10]([C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH:11][N:12]=2.O=P(Cl)(Cl)[Cl:27].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl>[Cl:27][C:6]1[C:7]2[C:8](=[N:9][C:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:11][N:12]=2)[N:23]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCc1cc(O)c2ncc(-c3ncccc3C(F)(F)F)nc2n1
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: COCc1cc(Cl)c2ncc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
6-Methoxymethyl-3-(3-trifluoromethyl-pyridin-2-yl)-pyrido-[2,3-b]pyrazin-8-ol (146 mg, 0.436 mmol) is dissolved in a solution of CHCl3 (20 mL), POCl3 (0.12 ml, 1.31 mmol) and 2,6-lutidine (0.2 mL, 1.31 mmol). The mixture is heated at reflux overnight. The reaction is concentrated under reduced pressure. EtOAc (30 mL) is added and the mixture is extracted with NaHCO3 (aq) (30 mL) and brine (30 mL). The organic extract is dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is purified by silica gel preparatory TLC eluting with hexanes/EtOAc (1:1) to yield the title compound as a light yellow oil that solidifies upon standing.
Reaction SMILES: [CH2:1]([CH:3]1[NH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2].[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>>[CH2:1]([CH:3]1[N:12]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:13])[CH:10]=2)[N:5]2[CH:14]=[CH:15][CH:16]=[C:4]12)[CH3:2]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CCC1Nc2cc(F)ccc2-n2cccc21
Product: CCC1c2cccn2-c2ccc(F)cc2N1C(=O)c1cccc(OC)c1

Procedure:
4-Ethyl-7-fluoro-5-(3-methoxybenzoyl)-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 17 and m-anisoyl chloride according to the procedure of Example 106, Step 2 mp 70-74° C. MS (ESI) m/z 351; Anal. Calcd for C21H19FN2O2: C, 71.99; H, 5.47; N, 7.99. Found: C, 70.08; H, 5.55; N, 7.14.
Reaction SMILES: Cl[C:2]1[N:20]=[CH:19][C:5]2[N:6]=[C:7]([CH3:18])[N:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1.C[O-].[Na+].[C:24](O)(=[O:26])C>CO>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[C:9](=[O:10])[C:4]3[CH:3]=[C:2]([O:26][CH3:24])[N:20]=[CH:19][C:5]=3[N:6]=[C:7]2[CH3:18])=[CH:12][CH:13]=1
Reactant: Cc1nc2cnc(Cl)cc2c(=O)n1-c1ccc(O)cc1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(=O)n(-c3ccc(O)cc3)c(C)nc2cn1
Yield: 88 %

Procedure:
6-chloro-3-(4-hydroxyphenyl)-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (300 mg, 1.04 mmol) was dissolved in dry methanol (15 mL) in a current of nitrogen, sodium methoxide (7 mmol) was added and the mixture was heated under reflux for 20 hours. After leaving to cool, acetic acid was added and the solvent was distilled off under reduced pressure. Distilled water was added to the residue, the solid precipitate was filtered off, and the title compound (259 mg, 88%) was thus obtained as a lavender color solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[N:7][CH:8]=1.[H][H]>[Pt](=O)=O.[Rh].C(O)(=O)C>[F:18][C:2]([F:1])([F:17])[CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:4]1
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(F)(F)F)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CNCC(C(F)(F)F)C1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
In a 50 mL hastalloy metal reactor, tert-butyl (5-(trifluoromethyl)pyridin-3-yl)carbamate (600 mg, 2.29 mmol) was treated with glacial acetic acid (10 mL), platinum (IV) oxide (250 mg, 1.10 mmol) and rhodium (5 wt. % (dry) on carbon, degussa type, 250 mg, 2.43 mmol) and hydrogenated at 200 psi hydrogen at 70° C. for 23 h. The reaction mixture was cooled to RT and filtered through a 0.45 um acrodisc, washed with MeOH and concentrated under reduced pressure. The residue was treated with EtOAc and 2N NaOH and extracted with EtOAc (3×25 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated to afford rac-tert-butyl (5-(trifluoromethyl)piperidin-3-yl)carbamate (490 mg, 1.83 mmol, 80%). MS (ESI, pos. ion) m/z: 269.1 (M+1). The crude material was used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(O)=[O:22].OO.S([O-])([O-])=O.[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:10]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:9])=[O:22]
Reactant: CSc1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Reactant: O=CO
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CS(=O)c1ccc([C@@H](CC2CCCC2=O)C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
A solution of 2(R)-(3-chloro-4-methylsulfanyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (683.2 mg, 2.18 mmol), formic acid (2.47 mL, 65.5 mmol), and water (0.41 mL) cooled to 0° C. was treated with a 30% aqueous hydrogen peroxide solution (1.11 mL, 10.9 mmol). The reaction was stirred at 0° C. for 1 h. At this time, the reaction was treated with a saturated aqueous sodium sulfite solution. The resulting solution was poured into water (50 mL) and was then extracted into methylene chloride (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2(R)-(3-chloro-4-methanesulfinyl-phenyl)-3-(2-oxo-cyclopentyl)-propionic acid (724 mg, 100%) as a white foam: EI-HRMS m/e calcd for C15H17ClO4S (M+Na)+ 351.0428, found 351.0433.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].C[O:8][C:9](=O)[C@@H:10]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([Br:23])[CH:17]=1)[C@H:11]([OH:13])[CH3:12].Cl>CO>[Br:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[C:15]([NH:14][C@H:10]([C:9]([NH:2][OH:3])=[O:8])[C@H:11]([OH:13])[CH3:12])=[O:24]
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(F)c(Br)c1)[C@@H](C)O
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@H](NC(=O)c1ccc(F)c(Br)c1)C(=O)NO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of hydroxylamine hydrochloride (66 mg, 0.95 mmol) in anhydrous MeOH (2.0 mL) at 0° C. under N2 atmosphere was added sodium methoxide (25 wt % in MeOH, 360 mg, 1.67 mmol). A precipitate formed immediately and the cloudy white solution was stirred for 10 minutes at 0° C. A solution of methyl (2S,3R)-2-[(3-bromo-4-fluorophenyl)carbonylamino]-3-hydroxybutanoate (2) (284 mg, 0.850 mmol) in MeOH (2.0 mL) was added and the reaction stirred 2 h at 0° C. and then warmed gradually to room temperature overnight (17 h total). Aqueous 1.0 M HCl (10 mL) was added and the solution extracted with 4:1 chloroform/isopropyl alcohol (4×20 mL). The organic layers were combined, dried over Na2SO4 and concentrated to give a pink foam. The crude solid was triturated with diethyl ether (2×8 mL) and dried in vacuo to give 3-bromo-4-fluoro-N-{(1S,2R)-2-hydroxy-1-[(hydroxyamino)carbonyl]propyl}benzamide 3 as a white foam: mp 152-153° C. Rf (10:1 CH2Cl2/MeOH on silica gel)=0.53.
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl>CCO>[CH:5]1[C:4]2[C:7]3[CH2:8][NH:3][CH2:4][CH2:5][C:6]=3[N:3]3[C:8]=2[C:7]([CH2:6][CH2:5][CH2:4]3)=[CH:7][CH:6]=1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1cc2c3c(c1)c1c(n3CCC2)CCNC1
Temperature: 25 °C
Yield: 298.5 %

Procedure:
1,2,3,4-Tetrahydroquinoylamine (0.925 g, 6.25 mmol) and 4-piperidone monohydrate hydrochloride (0.960 g, 6.25 mmol) were dissolved in EtOH (15 mL). Conc. HCl (0.52 mL, 6.25 mmol) was added. The reaction was refluxed for 3 hrs and then cooled to RT. The precipitate was collected by vacuum filtration. The residue was washed with 5 mL of EtOH, to afford the title compound (1.32 g, 85%) as a pure, white powder. 1H NMR (CD3OD, 300 MHz) δ7.22 (d, 1H, J=8.1 Hz), 6.92-6.97 (m, 1H), 6.86 (d, 1H, J=7.2 Hz), 4.87 (s, 2H), 4.05 (t, 2H, J=6.0 Hz), 3.61 (t, 2H, J=6.0 Hz), 3.14 (t, 2H, J=6.0 Hz), 2.94 (t, 2H, J=6.3 Hz), 2.16-2.24 (m, 2H) ppm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH2:12].[CH:13](=O)[CH2:14][CH2:15][CH3:16]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NCc1ccc2ccccc2c1
Reactant: CCCC=O
Product: CCCCNCc1ccc2ccccc2c1
Yield: 14.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 2-naphthalenemethanamine (500 mg, 3.18 mmol) and butyraldehyde (315 μL, 3.50 mmol) were converted to the title compound (100 mg, 15%). 1H NMR (CDCl3) δ 7.87-7.78 (m, 4H), 7.78-7.69 (br s, 1H), 7.56 (dd, J=8.4, 1.5 Hz, 1H), 7.52-7.43 (m, 2H), 4.06 (s, 2H), 2.78-2.69 (m, 2H), 1.65 (dt, J=15.4, 7.6 Hz, 2H), 1.38-1.23 (m, 2H), 0.88 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 214.1 (M+H)+.
Reaction SMILES: [CH:1]1([S:6]([C:9]2[N:14]=[CH:13][C:12]([C:15](=[N+]=[N-])[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(Cl)Cl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH:1]1([S:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(S(=O)(=O)C2CCCC2)nc1
Reactant: OC1CCOCC1
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Methyl 2-(6-cyclopentylsulfonyl-3-pyridyl)-2-diazo-acetate (0.25 g, 0.80 mmol) was dissolved in DCM (5 mL) under argon atmosphere. To this solution, 4-hydroxy tetrahydropyran (0.11 mL, 1.21 mmol) was added followed by rhodium (II) acetate dimer (9 mg, 0.021 mmol). Mixture was stirred at 25° C. for 60 min. Reaction mixture was diluted with DCM (10 mL), organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product (280 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:31])[CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[CH2:20]1.[C:32](OCC)(=[O:34])C>>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[NH:1][C:32](=[O:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH3:31])[CH:19]3[CH2:28][CH2:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH2:20]3)[CH2:13][CH2:12][C:3]=2[CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1)CC(N(C)CCCNCCc1cc(OC)c(OC)cc1N)CC2
Product: COc1ccc2c(c1)CC(N(C)CCCN1CCc3cc(OC)c(OC)cc3NC1=O)CC2

Procedure:
Here, 1-[2-(2-amino-4,5-dimethoxy-phenyl)-ethyl amino]-3-[N-methyl-N-(7-methoxy-1,2,3,4-tetrahydro naphth 2-yl)-amino]-propane (2.0 g, 0.005 mol) and N,N'-carbonyldiimidazole (1 g, 0.006 mol) are reflxed for 60 minutes in absolute ethyl acetate (40 ml). After extraction with saturated potassium carbonate solution and with water, the product which has been evaporated in vacuo is dissolved in methylene chloride and precipitated with petroleum ether. yield: 1.2 g. Mp: 163°-165° C.