Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[CH:15]1([S:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:28]([C@H:30]([CH3:39])[C@H:31]([OH:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH3:29])=[O:27])=[CH:21][CH:20]=2)[CH2:17][CH2:16]1.C(OC(=O)NC1C=CC=C(CN2C=CC(NC(=O)[C@@H](C3C=CC(S(C)(=O)=O)=C(Cl)C=3)[CH2:62][CH:63]3[CH2:67][CH2:66][CH2:65][CH2:64]3)=N2)C=1)(C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:63]1([CH2:62][C@H:25]([C:22]2[CH:21]=[CH:20][C:19]([S:18][CH:15]3[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[C:26]([N:28]([C@H:30]([CH3:39])[C@H:31]([OH:38])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:29])=[O:27])[CH2:67][CH2:66][CH2:65][CH2:64]1
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)Cc1ccc(SC2CC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](CC1CCCC1)c1ccc(SC2CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
A round bottom flask with a stir bar and argon inlet was charged with tetrahydrofuran (10 mL) and cooled to −78° C. 1,1,1,3,3,3-hexamethyldisilazane (1.2 mL, 5.69 mmol) was then added followed by the dropwise addition of a solution of n-butyl lithium (2.5M solution in hexanes, 2.12 mL, 5.32 mmol) and it was stirred at −78° C. for 15 min. After this time, a solution of 2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-acetamide (900 mg, 2.53 mmol) in tetrahydrofuran (6 mL) was added dropwise over 10 min keeping the reaction below −60° C. It was then stirred for 15 min, warmed to 0° C. and stirred for 20 min and then recooled to −78° C. It was then treated with a solution of iodomethylcyclopentane (prepared in PCT WO 2004/052869 A1 Example 1, 798 mg, 3.79 mmol) in 2,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (643 μL, 5.32 mmol) dropwise. The reaction was then stirred at −78° C. for 30 min and then warmed to 0° C. and stirred for 3 h. The reaction was then diluted with ethyl acetate (30 mL) and washed with a saturated aqueous ammonium chloride solution (3×10 mL). The aqueous layers were then combined and extracted with ethyl acetate (2×10 mL). The organics were then washed with a saturated aqueous brine solution (15 mL) and dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 25% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-propionamide (719 mg, 65%) as a clear colorless oil: [α]25589=−52.6° (c=0.19, methanol); ES-HRMS m/e calcd for C27H35NO2S (M+H)+ 438.2462, observed 438.2461.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38]>C1COCC1>[Br:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:24]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:25])[N:10]=2)=[CH:18][C:17]([O:22][CH3:23])=[CH:16][CH:15]=4)[CH:3]=1)=[O:38]
Reactant: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(N)c2)nc1=O
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(NC(=O)c3cccc(Br)c3)c2)nc1=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a mixture of 2-(3-amino-phenylamino)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (§) (20.0 mg, 0.06 mmol) in THF (2 mL), triethylamine (13 μL, 0.09 mmol) and 3-bromobenzoylchloride (10 μL, 0.07 mmol) was added and stirred at 50° C. for 2 hrs. The mixture was quenched with concentrated HCl and purified on BondElut® SCX (Varian Incorporated). Formed solid was washed with CH2Cl2 to give the title compound (25.3 mg, 81%). 1H-NMR (400 MHz, d6-DMSO) δ 10.43 (s, 1H), 9.68 (s, 1H), 8.15 (t, 1H), 8.08 (s, 1H), 7.97 (dt, 1H), 7.81 (ddd, 1H), 7.75 (brd, 1H), 7.70 (d, 1H), 7.51 (t, 1H), 7.36 (dt, 1H), 7.31 (t, 1H), 7.05-6.98 (2H), 6.42 (s, 1H), 3.99 (t, 2H), 3.84 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 517, 519.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].OC(C(F)(F)F)=O.[C:34]1([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][C:41]2=[O:46])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:43]4[CH2:44][CH2:45][N:40]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:41](=[O:46])[CH2:42]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: O=C1CNCCN1c1ccccc1
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(c4ccccc4)C(=O)C3)nn12
Temperature: 180 °C
Reaction time: 5 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1-phenylpiperazin-2-one TFA salt (133 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 5 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 1.0 min (conditions 4), MH+=485).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11]([NH2:14])(=[O:13])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)(=[O:13])=[O:12])=[O:24])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCCC2
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)CCCC2
Yield: 56 %

Procedure:
The title compound was prepared by the method of Example 1 in 56% yield from 5,6,7,8-tetrahydro-2-naphthalenesulfonamide and 4-chlorophenylisocyanate, m.p. 163°-165° C.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([NH2:14])=[S:13])([CH2:3][CH3:4])[CH3:2].Br[CH2:16][C:17](OC)=[O:18].[N+](C1C=CC([N:30]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[N:44]=[CH:43][N:42]([C:45]4[CH:50]=[CH:49][C:48]([O:51][C:52]([F:55])([F:54])[F:53])=[CH:47][CH:46]=4)[N:41]=3)=[CH:36][CH:35]=2)[C:31](=O)[O-:32])=CC=1)([O-])=O.CCN(C(C)C)C(C)C>CC(C)=O.C(OCC)C>[CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:17](=[O:18])[CH2:16][S:13]/[C:12]/1=[N:14]\[C:31]([NH:30][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:44]=[CH:43][N:42]([C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([F:53])([F:54])[F:55])=[CH:47][CH:46]=3)[N:41]=2)=[CH:36][CH:35]=1)=[O:32])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccccc1NC(N)=S
Reactant: COC(=O)CBr
Reactant: O=C([O-])N(c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCC(C)c1ccccc1N1C(=O)CS/C1=N\C(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.3 %

Procedure:
To a solution of 1-(2-(sec-butyl)phenylthiourea (1.40 g, 6.72 mmol) suspended in 5 mL of acetone was added methyl bromoacetate (1.23 g, 1.20 mmol), and the solution was allowed to stir at ambient temperature for 18 h. The solution was then diluted with 8 mL of diethyl ether and, after stirring for 30 min, the solvent was carefully decanted from a gummy oil. The intermediate, methyl 2-((N-(2-(sec-butyl)phenyl)carbamimidoyl)thio)acetate HBr (B8), was dissolved in 8 mL of dry tetrahydrofuran and 4-nitrophenyl(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamate (3.26 g, 6.72 mmol) was added, followed by Hünig's base (2.6 g, 20 mmol). The solution was allowed to stir at ambient temperature for 3 h, then it was concentrated and the residue chromatographed (silica gel, 0-70% EtOAc-hexanes) to give 730 mg (18%) of the title compound as a solid, mp 169-177° C.; 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.12 (d, J=8.7 Hz, 2H), 7.81-7.74 (m, 2H), 7.63-7.56 (m, 2H), 7.52 (m, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.41-7.32 (m, 3H), 7.28 (s, 1H), 7.11 (d, J=7.9 Hz, 1H), 4.03-3.95 (m, 2H), 2.43 (dd, J=13.5, 6.8 Hz, 1H), 1.73-1.56 (m, 2H), 1.20 (overlapping d, J=7.6 Hz, 3H), 0.78 (overlapping t, J=7.4 Hz, 3H); ESIMS m/z 594 ([M+H]+).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[S:14][C:15]([CH2:17][CH2:18][CH3:19])=[CH:16][C:3]1=2.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:17]([C:15]1[S:14][C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([C:12]4[NH:22][N:21]=[N:20][N:13]=4)=[CH:8][N:7]3[C:2](=[O:1])[C:3]=2[CH:16]=1)[CH2:18][CH3:19]
Reactant: CCCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc2c(=O)n3cc(-c4nnn[nH]4)ccc3nc2s1

Procedure:
From 0.85 g (0.0032 mol) of 4-oxo-2-propyl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile, (Example 29), 0.68 g (0.011 mol) of sodium azide and 0.62 g (0.012 mol) of ammonium chloride in 80 ml of dimethylformamide, following the procedure of Example b 34, there is obtained 0.46 g of 2-propyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one; mp 288°-292° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:19])[C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([N:8]([CH3:19])[C@H:9]2[CH2:10][CH2:11][C@H:12]([C:15]#[C:16][CH2:17][O:18][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:13][CH2:14]2)=[N:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](C#CCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 420 mg (1.3 mmol) of trans-3-{4-[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol in 10 ml CH2Cl2 was treated at 0° C. with 0.11 ml (1.43 mmol) methanesulfonylchloride, 0.16 ml (1.95 mmol) pyridine and 159 mg (1.3 mmol) DMAP. The reaction was stirred for 3.5 h at room temperature, water (2 ml) was added and stirred for 5 min. After extraction with aqueous saturated NaHCO3/Et2O(3×), the organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 540 mg (quantitative) of trans-Methanesulfonic acid 3-{4-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-prop-2-ynyl ester, MS: 402 (MH+, 1Br).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=O)[CH2:18][CH2:17]2)[S:6][C:7]=1[NH:8][C:9](=[O:15])[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])#[N:2].FC(F)(F)C(O)=O.[Cl:37][C:38]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:39]=1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.ClC(Cl)C>[C:1]([C:3]1[C:4]([CH3:29])=[C:5]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:43]3[CH:42]=[CH:39][C:38]([Cl:37])=[CH:45][C:44]=3[Cl:46])[CH2:18][CH2:17]2)[S:6][C:7]=1[NH:8][C:9](=[O:15])[CH:10]([CH2:11][CH3:12])[CH2:13][CH3:14])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1C#N
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)C(=O)Nc1sc(N2CCN(Cc3ccc(Cl)cc3Cl)CC2)c(C)c1C#N

Procedure:
To a solution of 1.06 g (2.52 mmol) of the title compound from Example 30 in 10 mL of CH2Cl2 was added 10 mL of trifluoroacetic acid. After 2 h at ambient temperature the reaction was concentrated in vacuo. To 0.040 g (0.092 mmol) of this intermediate in 1 mL of dichloroethane was added 0.055 g (0.20 mmol) of 2,4-dichlorobenzaldehyde, followed by 0.066 g (0.31 mmol) of sodium triacetoxyborohydride. After 16 h at ambient temperature the reaction was quenched by the addition of 10 mL of saturated aqueous NaHCO3. The reaction was extracted with CH2Cl2 and the organic layer was dried (Na2SO4) and concentrated in vacuo. Purification by preparative thin layer chromatography (15% EtOAc in hexane) afforded the title compound as a white solid. 1H NMR (500 MHz, CDCl3) 8.79 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 7.25 (dd, J=2.0 Hz, J=8.5 Hz, 1H), 3.64 (s, 2H), 2.94 (t, J=4.5 Hz, 4H), 2.63 (t, J=4.5 Hz, 4H), 2.28 (m, 1H), 2.16 (s, 3H), 1.73 (m, 2H), 1.61 (m, 2H), 0.95 (t, J=7.5 Hz, 6H); mass spectrum (ES) m/e=479.1 (M+H).
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH2:16])=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC#N>[C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([N:10]=[CH:11][C:12]([NH:16][S:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:31])=[O:30])=[CH:13]3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cnc2nn(-c3ccccc3)cc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cnc2nn(-c3ccccc3)cc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 3C (305 mg, 1.458 mmol) and pyridine (0.7 mL) in CH3CN (30 mL) cooled to 0° C. was added bezenesulfonyl chloride (274 mg, 1.550 mmol). After addition, the reaction mixture was stirred at RT for 1 hour, then concentrated under reduced pressure. The resultant residue was dissolved in CH2Cl2 (100 mL), washed with water (2×50 mL), saturated NaCl (50 mL). The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 2% of 2 M NH3 in MeOH/CH2Cl2 to give the title compound as a light brown solid (200 mg, 40% yield). LC/MS (method A): retention time=2.78 min, (M+H)+=351.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]=[CH:4]1)[CH3:2].[ClH:23].[NH2:24][OH:25]>O>[ClH:23].[CH2:1]([C:3]([CH2:21][CH3:22])([CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:5])[CH:4]=[N:24][OH:25])[CH3:2].[C:15]1([CH:6]([NH2:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:3]([CH2:21][CH3:22])([CH2:1][CH3:2])[CH2:4][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NO
Reactant: CCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1
Agent: Cl
Solvent: O
Product: CCC(C=NO)(CC)CC=CCCC=CCC(N)c1ccccc1
Product: CCC(CC)(CN)CCCCCCCCC(N)c1ccccc1

Procedure:
Reaction of 3,3-diethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene with hydroxylamine hydrochloride, in the presence of hydrochloric acid and water, to 2,2-diethyl-11-phenyl-11-amino-undeca-4,8-dienal-oxime, and hydrogenation of this to yield 1-phenyl-10,10-diethyl-1,11-diaminoundecane; b.p. 146° C./2 Pa; nD20 =1.5090.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11]3=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1.CCOC(C)=O>C1COCC1>[C:1]1([CH:7]2[N:12]3[C:32](=[O:33])[NH:17][C:13]4=[CH:14][CH:15]=[CH:16][C:10](=[C:11]34)[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc2c1NC(c1ccccc1)CO2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c2cccc3c2n1C(c1ccccc1)CO3
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
The 3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (0.95 g, 4.2 mmol) was dissolved in THF (30 mL) and DIPEA (1.5 mL, 8.4 mmol) at room temperature (room temperature). The N,N-carbonyldiimidazole (0.82 g, 5.0 mmol) was added portion wise over 10 min. The reaction was heated to 70° C. for 1 h and allowed to cool to room temperature and stirred overnight. To the reaction mixture was added EtOAc, and then the mixture was washed with water, sodium bicarbonate water and brine, then dried over magnesium sulfate and concentrated to give crude product as a dark oil. The oil was triturated with ethyl ether to give a precipitate. The solids were triturated twice with ethyl ether and then the solids were collected and air dried to give 4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a brown solid (0.51 g, 48%). LCMS calc. for C15H13N2O2 (M+H)+: m/z=253.1. found: 253.1. 1H NMR (300 MHz, DMSO-d6) δ 10.88 (s, 1H), 7.39-7.22 (m, 3H), 7.15-7.04 (m, 2H), 6.88 (t, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 5.45 (s, 1H), 4.54 (dd, J=11.6, 2.2 Hz, 1H), 4.37 (dd, J=11.6, 3.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](Cl)=[O:20])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([Cl:40])[C:32]=1[O:33][C:34]([F:39])([F:38])[CH:35]([F:37])[F:36])[NH2:29].C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH:29][C:28]3[CH:30]=[C:31]([Cl:40])[C:32]([O:33][C:34]([F:39])([F:38])[CH:35]([F:37])[F:36])=[C:26]([Cl:25])[CH:27]=3)=[O:20])=[CH:23][CH:24]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Cl
Reactant: Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1)C(=O)Nc1cc(Cl)c(OC(F)(F)C(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3.5 mmol of 2-(4-((3-chloro-5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy)propionyl chloride in 15 ml of methylene chloride was added dropwise to an ice-cooled solution prepared from 1.22 g (3.5 mmol) of an 80 percent solution of 3,5-dichloro-4-(1,1,2,2-tetrafluoroethoxy)aniline in DMF, 0.42 g (4.2 mmol) of triethylamine and 40 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight and then poured into a dilute aqueous HCl solution. The organic layer was separated, washed with a saturated aqueous NaHCO3 solution, dried over MgSO4 and evaporated to dryness. The residual material, a gum, was purified by preparative scale liquid chromatography, eluting with an 86:14 hexane:acetone mixture. After removal of the solvent, there was left 1.02 g (47 percent of theoretical) of the above-named product as a light yellow glassy material. The structure of the product was confirmed by its IR and NMR spectrum (NMR Spectrum: (d6 -DMSO); 8.55 (br, m, 1H); 8.45 (br, 1H); 7.9 (s, 2H); 6.6-7.2 (m, 5H); 4.9 (q, 1H); 1.6 (d, 3H). (Compound 2)
Reaction SMILES: N[C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[O:7][C:6]1=[O:25].N(OC(C)(C)C)=O.[I:42]I>C(Cl)(Cl)Cl.CCOC(C)=O>[F:22][C:21]([F:24])([F:23])[C:13]1[CH:12]=[C:11]([C@H:8]2[O:7][C:6](=[O:25])[N:5]([CH2:4][C:3]3[CH:26]=[C:27]([O:30][C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][C:2]=3[I:42])[C@H:9]2[CH3:10])[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1N
Reactant: II
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(OC(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4S,5R)-3-[2-amino-5-(trifluoromethoxy)benzyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (582 mg, 1.16 mmol) in CHCl3 (35 mL) was added t-butyl nitrite (275 μL, 2.32 mmol). After 10 minutes, I2 (736 mg, 2.9 mmol) was added. The reaction was stirred at room temperature for 30 minutes, and then heated to 65° C. for 2 hours. The reaction was then cooled to room temperature, diluted with EtOAc (150 mL) and washed with aqueous NaHSO3, water, brine, saturated NaHCO3, and brine (50 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (2 to 15% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.30 (15% EtOAc/hexanes). LCMS=614.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.89-7.91 (m, 2H), 7.79 (s, 2H), 7.23 (m, 1H), 6.95 (m, 1H), 5.75 (d, J=8.0 Hz, 1H), 4.81 (d, J=15.8 Hz, 1H), 4.32 (d, J=15.8 Hz, 1H), 4.07 (m, 1H), 0.78 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Li])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][CH:11]=1.O1CCCC1>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]([CH2:17][CH3:18])([OH:19])[C:13]2[CH:12]=[CH:11][C:10]([OH:9])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: [Li]c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(O)(c1ccc(O)cc1)c1ccc(Br)cc1

Procedure:
To 400 ml. of a 0.5 molar ethereal 4-bromophenyl-lithium solution a solution of 7.5 g. of 4'-hydroxy-propiophenone in 37 ml. of dry tetrahydrofurane is added dropwise, with stirring at a temperature between -50° C. and -40° C. The reaction mixture is stirred at 0° C. for an additional hour, and is then decomposed with a mixture of ice and glacial acetic acid. The aqueous phase is extracted with ether, the ethereal phases are combined, and washed to neutral with water. After drying over anhydrous magnesium sulfate the solvent is distilled off under reduced pressure, and the residue is chromatographed on a silica gel column with a 7:3 mixture of benzene and ethyl acetate as an eluting agent. The solvent is distilled off in vacuo, and the residue is crystallized from a mixture of ethyl acetate and dichloromethane. 4.2 g. of the named compound are obtained, melting at 161° to 162° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[C:22]2[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][C:17]=2[NH:16][N:15]=1.[CH:24](OCC)=[O:25]>O1CCCC1.CCCCCC>[OH:25][CH:24]=[C:20]1[CH2:19][CH2:18][C:17]2[NH:16][N:15]=[C:14]([CH3:13])[C:22]=2[C:21]1=[O:23]
Reactant: Cc1n[nH]c2c1C(=O)CCC2
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: Cc1n[nH]c2c1C(=O)C(=CO)CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 13.9 ml of diisopropylamine in 50 ml of anhydrous tetrahydrofuran there was added, by syringe, 38 ml of 2.6 N butyllithium in hexane. The mixture was cooled to -78° C. and a solution of 4.5 grams of 1,5,6,7-tetrahydro-3-methyl-4H-indazol-4-one was added dropwise. The mixture was stirred at -78° C. for 30 minutes and a solution of 10 ml of ethyl formate in 30 ml of anhydrous tetrahydrofuran was added dropwise. When the addition was complete, the reaction was allowed to warm to 0° C. and it was quenched by the dropwise addition of water (200 ml). After the mixture was stirred vigorously for a few minutes, the two layers which formed were separated. The aqueous layer was washed with ethyl ether and then acidified to a pH of about 4 with 5 N hydrochloric acid. The slurry which formed was extracted several times with dichloromethane and the combined extracts were dried and concentrated under reduced pressure to give 1,5,6,7-tetrahydro-5-hydroxymethylene-3-methyl-4H-indazol-4-one as a clammy yellow semi-solid.