Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=3)[CH:27]=[CH:26]2)[CH2:24][CH2:23]1.Cl.[O:40]=[C:41]1[NH:45][N:44]=[C:43]([C:46]2[CH:47]=[C:48]3[C:58](=[CH:59][CH:60]=2)[O:57][C:51]2([CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][C:49]3=[O:61])[NH:42]1>CN(C=O)C.O.CCN(CC)CC>[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([N:54]4[CH2:55][CH2:56][C:51]5([CH2:50][C:49](=[O:61])[C:48]6[C:58](=[CH:59][CH:60]=[C:46]([C:43]7[NH:42][C:41](=[O:40])[NH:45][N:44]=7)[CH:47]=6)[O:57]5)[CH2:52][CH2:53]4)=[O:36])[CH:32]=3)[CH:27]=[CH:26]2)[CH2:23][CH2:24]1
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3n[nH]c(=O)[nH]3)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4n[nH]c(=O)[nH]4)ccc2O3)cc2c1ccn2C1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Et3N (209 uL), HOBT (91.2 mg) and WSC (115 mg) were added to a suspension of 1-cyclopropyl-4-(methyloxy)-1H-indole-6-carboxylic acid (116 mg) and 6-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (202 mg) in DMF (3 mL), and the mixture was stirred overnight at 50° C. Water was added to the reaction mixture, and the formed solid was collected by filtration. The solid was purified by silica gel column chromatography (CHCl3/MeOH) to obtain the intended compound as colorless foam. 1H-NMR (400 MHz, DMSO-d6) δ: 8.06 (1H, d, J=2.3 Hz), 8.00 (1H, dd, J=8.7, 2.3 Hz), 7.29 (1H, d, J=3.2 Hz), 7.26 (1H, d, J=8.7 Hz), 7.24-7.21 (3H, m), 6.58 (1H, d, J=1.0 Hz), 6.40 (1H, dd, J=3.2, 1.0 Hz), 4.44-4.08 (1H, br m), 3.87 (3H, s), 3.80-3.25 (4H, m), 2.97 (2H, s), 2.10-1.70 (4H, m), 1.09-1.01 (2H, m), 0.96-0.89 (2H, m); MS [M+H]+=514.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:21])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[S:28](Br)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:21][S:28]([C:31]3[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(S)c(C(C)(C)C)cc21
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Sc2cc3ccn(C(=O)OC(C)(C)C)c3cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to General Method 15 using 6-tert-butyl-5-mercapto-indole-1-carboxylic acid tert-butyl ester (prepared in Example FF), pyridine, tosyl bromide, carbon tetrachloride, and EtOAc.
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:13])=[CH:3][C:2]2=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:18]([Cl:33])=[CH:17][N:16]=1>>[CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:15]3[N:20]=[C:19]([NH:21][C@@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]4[NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:18]([Cl:33])=[CH:17][N:16]=3)=[CH:3][C:2]2=1
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl

Procedure:
Following a procedure analogous to 61e, 12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (200 mg, 1.15 mmol) and N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (389 mg, 1.15 mmol) were converted to the title compound isolated as an ivory solid (430 mg, 78%) %), isolated as a mixture of diastereomers. 1HNMR (400 MHz, DMSO-d6) δ 9.1 (s, 1H), 7.9 (s, 1H), 7.5 (s, 0.5H), 7.4 (s, 0.5H), 7.3 (appt t, 1H, J=7.8 Hz), 7.2 (d, 0.5H, J=8.1 Hz), 7.1 (d, 0.5H, J=8.3 Hz), 6.9 (d, 1H, J=8.3 Hz), 6.7 (d, 1H, J=7.3 Hz), 4.1 (d, 0.5H, J=4.0 Hz), 4.0 (d, 0.5H, J=3.4 Hz), 3.9-3.8 (m, 1H), 3.7 (m, 1H), 3.4 (m, 1H), 3.0 (d, 1H, J=4.5 Hz), 2.9 (d, 3H, J=7.3 Hz), 2.5-2.4 (m, 2H), 2.1-2.0 (m, 2H), 1.9 (m, 2H), 1.8-1.6 (m, 3H), 1.5-1.2 (m, 5H); MS (m/e) 477 (M+1); mp 150-154° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][C:9]([N:18]([CH3:20])[CH3:19])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].[Cl-].C[O:23]C1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH:39]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([CH:48]([CH2:52][CH3:53])[C:49](O)=O)=[CH:40]1>CO>[CH3:19][N:18]([CH3:20])[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:11][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:53](=[O:23])[CH2:52][CH:48]([C:41]2[C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[NH:39][CH:40]=2)[CH3:49])=[O:4])[CH2:7][CH2:8]1
Reactant: CCC(C(=O)O)c1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)CN)CC1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: CC(CC(=O)NCC(=O)NC1CCC(c2ccccc2)(N(C)C)CC1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The more polar diastereomer of 2-amino-N-(4-dimethylamino-4-phenylcyclohexyl)-acetamide (159 mg, 0.57 mmole) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (239 mg, 0.86 mmole) were added to a solution of indol-3-yl-butyric acid (117 mg, 0.57 mmole) in MeOH and stirred for 24 h at room temperature. Working up was performed by removing MeOH by distillation. The batch was re-dissolved with water, adjusted to pH 11 with 5M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and evaporated. The more polar amide was obtained as a colorless oil in a yield of 265 mg (100%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[OH-:16].[Na+]>CCOCC>[S:11]([NH:3][CH2:2][CH2:1][NH:4][S:11]([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:12])=[O:16])([C:8]1[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [OH-]
Reactant: NCCN
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NCCNS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Treat ethylenediamine with p-toluenesulfonyl chloride (i.e. tosyl chloride) and sodium hydroxide in aqueous ether according to known procedures to obtain N,N'-ditosylethylenediamine.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28].O>C1COCC1>[Cl:1][C:2]1[N:11]2[C:27](=[S:28])[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Clc1nc(NNc2ccccc2)c2ccccc2n1
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=c1n(-c2ccccc2)nc2c3ccccc3nc(Cl)n12
Reaction time: 0.08 h

Procedure:
To a mixture of 2-chloro-4-phenylhydrazinoquinazoline (example I) (600 mg, 2.2 mmol) and triethylamine (800 ml, 5.7 mmol) in THF (50 ml) was added thiophosgene (180 ml, 2.3 mmol) slowly and stirred for additional 5 min. The reaction mixture was poured into water and extracted with CH2 Cl2 (3×50 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The residue was triturated with ethanol and the precipitate was filtered to afford 5-chloro-2-phenyl-1,2,4-triazolo[4,3-c]quinazolin-3-thione.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[CH:10].CCCCCC.C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[Br:33][CH2:34][CH2:35][CH2:36]Br>O1CCCC1>[Br:33][CH2:34][CH2:35][CH2:36][C:10]#[C:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: BrCCCBr
Reactant: C#CCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: BrCCCC#CCOC1CCCCO1
Temperature: -10 °C
Yield: 47.9 %

Procedure:
Under argon flow, 13.46 g of 3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne was dissolved in 135 ml of anhydrous tetrahydrofuran, and 60 ml of 1.6 N n-butyllithium hexane solution was added dropwise over 20 minutes with stirring at −10° C. of inner temperature. The mixture was stirred for 1 hour at the same temperature. After stirring for additional 1 hour at room temperature, the inner temperature was changed to −3° C., and 16.7 ml of hexamethylphosphoric triamide (HMPA) was added to the mixture. Then 58.14 g of 1,3-dibromopropane was added in a portion at −10° C. of inner temperature, and the mixture was stirred for 12 hours at room temperature. The reaction solution was poured into ice-cold water, extracted with ether, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under reduced pressure to give 12.0 g of the objective compound as colorless oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.C([Li])CCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1>[Cl:7][C:4]1[S:3][C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:6][CH:5]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ccc(Br)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(Cl)s1
Temperature: -80 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A stirred solution of 5.1 mL (0.046 mole) of 2-bromo-5-chlorothiophene in 200 mL of tetrahydrofuran was cooled to -85° C., and 19.7 mL (0.049 mole) of n-butyllithium (0.049 mole--2.5M in hexanes) was added dropwise during a 15 minute period. The reaction mixture temperature was maintained at -85° C. to -80° C. throughout the addition. Upon completion of addition, the reaction mixture temperature was maintained at about -80° C. for one hour. After this time, a solution of 12.5 mL (0.046 mole) of tributyltin chloride in 50 mL of tetrahydrofuran was added to the cold reaction mixture during a 10 minute period. Upon completion of addition, the reaction mixture was stirred at -80° C. for one hour, then it was allowed to warm gradually to ambient temperature. The reaction was quenched with an aqueous solution saturated with ammonium chloride, and then the reaction mixture was extracted with three 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 18.4 grams of (5-chlorothien-2-yl)tributyl tin. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:8][CH2:7][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-])=O)[CH2:5][CH2:4][CH:3]1[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:68]([O:72][C:73]([NH:75][C:76]1[S:80][C:79]([C:81]2[C:86]([F:87])=[CH:85][CH:84]=[CH:83][C:82]=2[F:88])=[N:78][C:77]=1[C:89](O)=[O:90])=[O:74])([CH3:71])([CH3:70])[CH3:69]>CO.C(Cl)Cl.[Pd]>[F:1][C:2]1([F:25])[CH:3]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:4][CH2:5][N:6]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:89]([C:77]2[N:78]=[C:79]([C:81]3[C:82]([F:88])=[CH:83][CH:84]=[CH:85][C:86]=3[F:87])[S:80][C:76]=2[NH:75][C:73](=[O:74])[O:72][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:90])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)C(F)(F)F)C(F)(F)CC1
Agent: [Pd]
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC(NC(=O)C(F)(F)F)C(F)(F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
A solution of N-(5,5-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide (0.29 g, 0.78 mmol) in MeOH (20 mL) was passed through the H-Cube®(Full H2 Mode, 70° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to give the crude amine. To a solution of this amine (0.26 g, 0.78 mmol) in DCM (15 mL) was added DIPEA (0.68 mL, 3.9 mmol), PyBOP (0.61 g, 1.17 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (0.30 g, 0.86 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 4-(5-(4,4-difluoro-5-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as a white solid (0.37 g, 69%). 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.71 (s, 1H), 7.82 (s, 1H), 7.42-7.33 (m, 1H), 7.11-7.01 (m, 2H), 6.72 (d, J=9.0 Hz, 1H), 4.73-4.57 (m, 1H), 3.77 (s, 3H), 3.51-3.37 (m, 2H), 3.36-3.25 (m, 2H), 2.49-2.36 (m, 2H), 2.25-2.03 (m, 2H), 1.55 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:16][NH:17][CH3:18]>C(Cl)Cl.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12]([N:17]([CH3:18])[CH3:16])(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CNC
Reactant: CS(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of (4-methanesulfonyl-phenyl)-methanesulfonyl chloride from Step 2 (1.0 g, 3.7 mmol) in CH2Cl2 (40 mL) was added dimethylamine (0.42 g, 9.3 mmol) dropwise. After 18 h, the resulting reaction mixture was diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (HCl 10%, NaHCO3, brine), dried (MgSO4), filtered, and concentrated to provided the C-(4-methanesulfonyl-phenyl)-N,N-dimethyl-methanesulfonamide compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](OO)=O)[CH:3]=1.C(S[C:20]1[N:25]=[C:24]([N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[S:27]([N:30]2[CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[C:22]([NH:42][C@H:43]([CH3:46])[CH2:44][OH:45])[N:21]=1)C1C=CC=CC=1.[S:47]([O-:51])([O-:50])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:8]([S:47]([C:20]1[N:25]=[C:24]([N:26]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:40])[CH3:41])[S:27]([N:30]2[CH2:31][CH2:32][CH2:33]2)(=[O:29])=[O:28])[CH:23]=[C:22]([NH:42][C@H:43]([CH3:46])[CH2:44][OH:45])[N:21]=1)(=[O:51])=[O:50])[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: O=S([O-])([O-])=S
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCC2)nc(SCc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCC2)nc(S(=O)(=O)Cc2ccccc2)n1
Reaction time: 1 h

Procedure:
m-Chloroperbenzoic acid was added as a single portion to a solution of the subtitle product of step iii) (11.3 g) in DCM (500 ml) and stirred for 1 h. Saturated sodium thiosulfate solution (100 ml) was added and stirred vigourously until no peroxide was detected. The organics were separated and extracted with saturated sodium bicarbonate solution (200 ml) and brine (50 ml), dried (MgSO4) and concentrated to yield the subtitle compound as a crude solid. Yield: 10.9 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[OH:12].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)=[O:21])[CH2:16][CH2:15]1>CO.C(OCC)(=O)C>[OH:12][CH:5]1[CH2:6][CH2:7][NH:8][C:9]2[N:10]=[CH:11][C:2]([C:25]3[CH:24]=[CH:23][C:22]([C:20]([N:17]4[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]4)=[O:21])=[CH:27][CH:26]=3)=[CH:3][C:4]1=2
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: OC1CCNc2ncc(Br)cc21
Solvent: CO
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Yield: 49 %

Procedure:
6-Bromo-1,2,3,4-tetrahydro-[1,8]naphthyridin-4-ol (300 mg) was reacted with (4-methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]methanone (450 mg) as in General Procedure 13. Basic alumina chromatography using a gradient of 0-10% methanol/ethyl acetate as the eluting solvent gave the title compound as a white foam (49% yield). LCMS: m/z=353 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.78 (m, 1H), 2.19 (s, 3H), 2.32 (bs, 4H), 3.27 (m, 1H), 3.36 (m, 1H), 3.50 (bs, 4H), 4.65 (m, 1H), 5.27 (d, J=4.8 Hz, 1H), 6.81 (s, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.62 (d, J=8.3 Hz, 2H), 7.71 (d, J=2.2 Hz, 1H), 8.22 (d, J=2.2 Hz, 1H).
Reaction SMILES: [C:1]1(=[O:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[O:13].[Br:15]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[Br:15][C:9]1[CH:8]=[C:7]2[C:12]3=[C:11]([C:1](=[O:14])[C:2](=[O:13])[N:3]3[CH2:4][CH2:5][CH2:6]2)[CH:10]=1
Reactant: O=C1C(=O)N2CCCc3cccc1c32
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(=O)N2CCCc3cc(Br)cc1c32
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (10 g) and N-bromosuccinimide (10 g) in DMF (60 ml) was stirred at 70° C. for 5 hours. After cooling, to the mixture was added ethyl acetate (500 ml) and washed with water and saturated aqueous sodium chloride solution successively, and then dried over anhydrous sodium sulfate. Evaporation of ethyl acetate afforded the title compound The compound was recrystallized from ethanol to give 14 g (98.4%) as dark red needles.
Reaction SMILES: Cl[C:2]1[CH:23]=[C:22]([F:24])[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:5].[CH2:28](OB(C=C)OCCCC)[CH2:29]CC.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.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>[F:24][C:22]1[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][C:3]([C:4]([NH:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[O:5])=[C:2]([CH:28]=[CH2:29])[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc([N+](=O)[O-])c(F)cc2Cl)CC1
Reactant: C=CB(OCCCC)OCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1cc(F)c([N+](=O)[O-])cc1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C

Procedure:
Under nitrogen, the mixture of tert-butyl 4-(2-chloro-4-fluoro-5-nitrobenzamido)piperidine-1-carboxylate (Step 1, 1.52 g, 3.88 mmol), vinylboronic acid dibutyl ester (0.86 mL, 3.88 mmol), dichlorobis(triphenylphosphine)palladium (II) (136 mg, 0.2 mmol) and sodium carbonate (2.9 g, 27.2 mmol) in THF (40 mL) and water (10 mL) was heated at 90° C. overnight. The reaction mixture was cooled to room temperature, partitioned between EtOAc and brine. The organic extracts were dried (Na2SO4), concentrated, and purified by silica gel chromatography (EtOAc/Hexanes:1/4) to afford tert-Butyl 4-(4-fluoro-5-nitro-2-vinylbenzamido)piperidine-1-carboxylate; ESMS m/z 394.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][OH:36])=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][OH:36])=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: OCCNc1ccc(Br)cn1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: OCCNc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 g, 1.0 mmol) and 2-(5-bromo-pyridin-2-ylamino)-ethanol (example B.46) (195 mg, 0.9 mmol) according to general procedure II. Obtained as a red solid (50 mg, 10%). MS (ISP) 492.0 [(M+H)+]; mp 202-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])[CH:22]=[C:21]([Cl:31])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[N:19][OH:20])[C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[CH3:32][O:20][N:19]=[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:24][C:23]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])=[CH:22][C:21]=2[Cl:31])=[CH:10][CH:11]=1)[C:16](=[O:18])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)C(=NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(C)=O)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
0.8 g of 1-(4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-phenyl)-propane-1,2-dione 1-oxime, 0.43 g of potassium carbonate and 0.26 g of methyl iodide are stirred in 10 ml of dimethylformamide at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate. After concentration of the organic phase and purification over silica gel, the title compound is obtained. 1H-NMR (CDCl3) 300 MHz: 2.30 (m, 2H), 2.51 (s, 3H), 4.08 (s, 3H), 4.15 (t, 2H), 4.29 (t, 2H), 4.59 (d, 2H), 6.11 (t, 1H), 6.83 (s, 2H), 6.95 (d, 2H), 7.30 (d, 2H)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13][O:14][C:15](=[O:21])[C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.ON1C2C=CC=C[C:26]=2N=N1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:13]([O:14][C:15]([C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)=[O:21])[CH3:26]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H]1CCCN1C(=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 3-hydroxy phenylacetic acid (1.52 g, 10.0 mmol) in 10 mL of DCM is added L-proline methyl ester hydrochloride (1.80 g, 10.0 mmol) followed by the addition of TEA (1.67 mL, 12 mmol), 1-hydroxybenzotriazole (HOBt, 1.17 g, 10 mmol), and EDCl (1.92 g, 10 mmol). The mixture is stirred at RT for 4 days. Ethyl acetate and water is added, and the organic layer is separated and washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude mixture is purified by flash chromatography (silica gel) eluting with hexane:ethyl acetate (1:2) to give (R)-1-[2-(3-hydroxy-phenyl)-acetyl]-pyrrolidine-2-carboxylic acid ethyl ester as an oil.