Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>COCCOC.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>[NH2:33][C:30]1[CH:29]=[CH:28][C:27]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:32][C:31]=1[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cc(N3CCCCC3)ccc2N)OC1(C)C
Reactant: O=C(Nc1ccnc(Cl)c1)c1cccc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(N2CCCCC2)cc1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-chloropyridin-4-yl)-3-(trifluoromethyl)benzamide (350 mg, 1.16 mmol, 1.00 equiv), 4-(piperidin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (430 mg, 1.42 mmol, 1.20 equiv), Pd(PPh3)2Cl2 (81.7 mg, 0.12 mmol, 0.10 equiv), K3PO4.7H2O (790 mg, 2.33 mmol, 2.00 equiv), X—PHOS (91.6 mg, 0.23 mmol, 0.20 equiv) in DME/H2O (10:1) (30/3 mL). The resulting solution was stirred for 2 h at 80° C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residual solution was diluted with 50 mL of water. The resulting solution was extracted with 2×50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (100˜100:1˜40:1). This resulted in 350 mg (67%) of N-(2-(2-amino-5-(piperidin-1-yl)phenyl)pyridin-4-yl)-3-(trifluoromethyl)benzamide as a yellow solid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.C([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: COc1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(CN2CCNCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
A mixture of 2.0 g 3-methoxy benzylchloride, 2.9 g 1-Boc piperazine, 5 mL triethylamine, and 20 mL tetrahydrofuran was stirred at room temperature for 20 minutes. The mixture was concentrated, and the residue was added to 20 mL trifluoroacetic acid and stirred at room temperature for 20 minutes. The trifluoroacetic acid was evaporated, and the residue was suspended in methanol and neutralized with an aqueous saturated sodium bicarbonate solution. The solvent was evaporated, and the residue was suspended in dichloromethane and purified by NH silica gel chromatography to give 2.4 g of the title compound as a white solid.
Reaction SMILES: [H-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:17][C:18]1[S:22][C:21]([C:23](=[O:25])[CH3:24])=[CH:20][C:19]=1[CH3:26].CC(OC)(C)C>C1COCC1>[Br:17][C:18]1[S:22][C:21]([C:23](=[O:25])[CH2:24][C:11]([C:6]2[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=2)([OH:16])[C:12]([F:13])([F:14])[F:15])=[CH:20][C:19]=1[CH3:26]
Reactant: CC(=O)c1cc(C)c(Br)s1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)sc1Br
Reaction time: 2 h
Yield: 111.4 %

Procedure:
LiH (2.06 g) is added to a solution of 3′,5′-dichloro-2,2,2-trifluoroacetophenone (48.0 g) and 1-(5-bromo-4-methyl-thiophen-2-yl)-ethanone (30.3 g) in THF (1000 ml). After 2 hours at 60° C. MTBE is added (300 ml) and the reaction mixture is poured onto water (500 ml) at 0° C. The organic phase is extracted with water and a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 71.2 g of 1-(5-bromo-4-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-hydroxy-butan-1-one. The crude product is used without further purification.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43](O)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:65][N:66]1[CH2:72][CH:71]2[NH:73][CH:68]([CH2:69][CH2:70]2)[CH2:67]1>CN(C=O)C>[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][C:41]([C:43]([N:73]4[CH:68]5[CH2:69][CH2:70][CH:71]4[CH2:72][N:66]([CH3:65])[CH2:67]5)=[O:44])=[CH:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CN1CC2CCC(C1)N2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)=Cc1ccccc1-3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1C2CCC1CN(C)C2)=Cc1ccccc1-3

Procedure:
TBTU (115 mg, 0.361 mmol) was added at rt, in one portion, to a solution containing 13-cyclohexyl-10-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (100 mg, 0.241 mmol), DIEA (0.17 mL, 0.964 mmol), 3-Methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (115 mg, 0.289 mmol), and DMF (2.4 mL). The solution was maintained for 18 h and concentrated. The resultant residue was charged with dichloromethane (30 mL), washed with water (4×15 mL), washed with brine (15 mL), dried (magnesium sulfate), filtered and concentrated to afford a yellow solid which was used without further purification in the next step. LCMS: retention time: 2.272 min LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% CH3CN/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% CH3CN/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode: m/z 524 (MH+). Crude 1H NMR (300 MHz, CDCl3) δ ppm: 8.19 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.77 (dd, J=8.78 Hz, J=1.46 Hz, 1H), 7.61 (m, 1H), 7.49 (m, 3H), 6.96 (s, 1H), 5.2 (s, 1H), 4.41 (s, 1H), 2.81 (m, 4H), 2.51 (s, 1H), 1.95 (m, 15H), 1.29 (m, 11H), 0.76 (m, 2H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:28]1CCO[CH2:30][CH2:29]1.C(S(C1C=C(C2C=C(CN(C)C)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21][NH:28][CH2:29][CH3:30])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: C1COCCN1
Agent: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Product: CCNCc1cc(-c2cccc(S(=O)(=O)CC)c2)c2c(c1)[nH]c1ncc(C)cc12

Procedure:
The title compound was prepared from Compound 133 and morpholine according to the procedure outline for the preparation of Compound 134. 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H, J=7.6 Hz), 7.97 (d, 1H, J=7.6 Hz), 7.84 (t, 1H, J=7.6 Hz), 7.64 (s, 1H), 7.54 (s, 1H), 7.22 (s, 1H), 4.25 (s, 2H), 3.34 (q, 2H, J=7.2 Hz), 2.99-3.07 (m, 2H), 2.25 (s, 3H), 1.20-1.29 (m, 6H). MS (ES) [m+H] calc'd for C23H25N3O2S, 408; found 408.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:12]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([OH:25])=O)[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CC[N:28]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[N:11]=[C:10]([C:18]3[CH:19]=[C:20]([C:23]([NH2:28])=[O:25])[S:21][CH:22]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ncc(Br)c2c1c(-c1csc(C(=O)O)c1)nn2C1CCCC1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Br)c2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Yield: 88.2 %

Procedure:
A solution of 4-(7-bromo-1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (100 mg), HOBt ammonium salt (227 mg) and EDCI hydrochloride (180 mg) in DMF (15 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) to give the title compound (88 mg).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]>Cl>[Cl:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: C1=COCCC1
Reactant: OCCCCCl
Agent: Cl
Product: ClCCCCOC1CCCCO1
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Dihydropyran (15.5 g) was added dropwise to a mixture of 4-chlorobutanol (20 g) and hydrochloric acid (18 M, 1 drop) at RT. The mixture was stirred for 30 min and washed with H2O (100 ml), aqueous NaHCO3 (1 M, 50 ml) and BR (50 ml). The dried liquid was heated under reduced pressure to leave the title compound as a colourless liquid (31.9 g). T.l.c. [L] Rf 0.5.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:12]([O-])=O.[NH:15]1[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:17][CH2:16]1>>[NH2:12][C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:2]=1[N:15]1[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])[CH2:17][CH2:16]1
Reactant: O=C(N[C@@H]1CCCNCC1)C(F)(F)F
Reactant: O=[N+]([O-])c1cnn(CC(F)(F)F)c1Br
Product: Nc1cnn(CC(F)(F)F)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 53.6 %

Procedure:
Following the procedure for Intermediate 8 starting from 5-bromo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (150 mg, 0.55 mmol) and (R)—N-(azepan-4-yl)-2,2,2-trifluoroacetamide (115 mg, 0.55 mmol) gave (R)—N-(1-(4-amino-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide as a colourless gum (110 mg, 53%). 1H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.11 (br s, 1H), 4.54 (q, J=8.5 Hz, 2H), 4.35-4.22 (m, 1H), 3.40-3.23 (m, 2H), 3.21-3.08 (m, 2H), 2.62 (br s, 2H), 2.17-2.08 (m, 1H), 2.06-1.91 (m, 1H), 1.92-1.71 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:5]=[C:4]([F:12])[C:3]=1[OH:13].[CH2:14]([O:16][C:17](=[O:21])[C:18]#[C:19][CH3:20])[CH3:15].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:14]([O:16][C:17](=[O:21])/[CH:18]=[C:19](/[O:13][C:3]1[C:4]([F:12])=[CH:5][CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]=1[F:1])\[CH3:20])[CH3:15]
Reactant: CC#CC(=O)OCC
Reactant: CC(C)Oc1ccc(F)c(O)c1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1c(F)ccc(OC(C)C)c1F
Yield: 73.6 %

Procedure:
To a stirred mixture of 2,6-difluoro-3-isopropoxy-phenol (5.74 g, 0.031 mol) and ethyl-2-butynoate (6.85 g, 0.061 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated which afforded (E)-3-(2,6-difluoro-3-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester as a brown oil (6.85 g, 75%) and used without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]2[CH:21]([C:22]([O-:24])=[O:23])[NH:20][CH2:19][CH2:18][CH2:17][S:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH:15]2[CH:21]([C:22]([OH:24])=[O:23])[NH:20][CH2:19][CH2:18][CH2:17][S:16]2)(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2SCCCNC2C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2SCCCNC2C(=O)O)cc1

Procedure:
Following the procedure of Step 3 of Example 173, tert-butyl(3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylate (800 mg, 1.88 mmol), trifluoroacetic acid (6 mL) in methylene chloride (15 mL) provide 650 mg (94%) of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-1,4-thiazepane-3-carboxylic acid; 1H NMR (300 MHz, acetone-d6): δ 1.74 (m, 3H), 1.90 (m, 2H), 2.59 (m, 2H), 2.90 (m, 1H), 3.18 (m, 1H), 3.26 (m, 1H), 3.70 (m, 1H), 4.70 (m, 3H), 7.03 (d, 2H, J=8.7 Hz), 7.77 (d, 2H, J=8.7 Hz); HRMS (C16H19NO5S2)(M+H); calcd. 370.0777, found 370.0765.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:30])[CH3:29])=[CH:24][C:23]=1[S:31]([CH3:34])(=[O:33])=[O:32]>C(#N)C.C(N(CC)C(C)C)(C)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:30][CH:28]([C:25]4[CH:26]=[CH:27][C:22]([CH3:21])=[C:23]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:24]=4)[CH3:29])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: Cc1ccc(C(C)N)cc1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(NC(C)c4ccc(C)c(S(C)(=O)=O)c4)c3C2)c(C#N)c1
Yield: 49.9 %

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (360 mg, 1.26 mmol) and 1-(4-methyl-3-(methylsulfonyl)phenyl)ethanamine (400 mg, 1.88 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (1 mL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to afford a light yellow solid (290 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.OO.NC(N)=[O:13].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N+:3]=1[O-:13]
Reactant: Brc1cccc(Br)n1
Reactant: NC(N)=O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1c(Br)cccc1Br
Temperature: 5 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
2,6-dibromo pyridine (79 g, 334 mmol) was dissolved in 800 ml of dry dichloromethane and cooled under nitrogen to 5° C. then urea hydrogen peroxide (104 g, 1.1 mol) was added in one portion. When the mixture had cooled again to 3° C., a solution of trifluoro acetic acid anhydride (140 mL, 1 mol) in 100 ml DCM was added via dropping funnel over 45 min, whilst keeping the temperature between 5-7° C. The mixture was allowed to warm to room temperature and stirred for 20 hours. The mixture was cooled in an ice bath to 10° C. and 10% aq. Na2SO3 (˜50 g/500 ml) was added dropwise over 60 minutes until test with starch iodide paper was negative. The resulting mixture was filtered to remove a quantity of fluffy solid and the layers were separated. The aqueous layer was extracted with dichloromethane (2×200 ml) and the combined extracts were dried over MgSO4 and concentrated under reduced pressure to give a light brown solid. Recrystallisation of crude product using 600ml of boiling acetone gave 48.47 g of the title compound.
Reaction SMILES: C1([Li])C=CC=CC=1.[Cl-].[CH3:9][O:10][CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[CH:32]=1.[Cl-].[NH4+]>CCOCC>[CH3:9][O:10][CH:11]=[CH:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Li]c1ccccc1
Agent: [NH4+]
Solvent: CCOCC
Product: COC=Cc1cccnc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
Phenyllithium (111 ml of 1.8M solution in ether) was added dropwise to a stirred suspension of (methoxymethyl) triphenylphosphonium chloride (68.6 g) in dry ether (600 ml) at -50° C. The mixture was stirred at -50° C. for 2 hours and then allowed to reach 0° C. over 30 minutes. 3-Pyridinecarboxaldehyde (10.70 g) was added dropwise with stirring, and the mixture was stirred at room temperature for 18 hours. Anexcess of ammonium chloride solution was then added and the layers were separated. The aqueous layer was separated and washed with ether, and the organic layers were combined and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel initially using ethyl acetate/hexane (1:4) as eluant. The polarity was gradually increased to ethyl acetate/hexane (1:1) to give the pure product as an oil(8.82 g) which was used directly in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:30][C:31]#[CH:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:28])[C:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][O:17][CH2:32][C:31]#[CH:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C#CCCl
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOC=C(C(=O)NCCc1ccc(OC)c(OC)c1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Yield: 63 %

Procedure:
Six hundred milligrams (600 mg) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (1.57 mmol), 0.14 g (1.89 mmol) of 3-chloropropyne, 280 mg (2.05 mmol) of potassium carbonate and 10 ml of anhydrous N,N-dimethylformamide were mixed and stirred at room temperature. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=1:1) to give 415 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-(2-propynyloxy)-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1196).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19]>CC#N.C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OCCNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 90.1 %

Procedure:
To a solution of Compound 2 (1.86 g, 12.3 mmol) and potassium carbonate (1.70 g, 12.3 mmol) in CH3CN anhydrous (50 mL) at 0° C. was dropwise added t-Butyl-bromoacetate (2.41 g, 12.4 mmol) over 45 minute. The reaction mixture was gradually warmed to room temperature and stirred for 66 h. The resulting reaction mixture was filtered, and the filtrate was concentrated to give a white oily compound. The residue was then dissolved in CH2Cl2 (50 mL), and the resulting solution was filtered, and the filtrate was concentrated to afford white Compound 4 (2.94 g, 90%), 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.86 (t, 2H), 3.23 (s, 2H), 3.54 to 3.62 (m, 2H), 3.82 (s, 2H), 7.23 to 7.34 (m, 5H); 13C NMR (CDCl3) δ 28.00, 55.27, 26.52, 58.47, 58.84, 81.29, 127.28, 128.36, 128.81, 138.27, 171.02. HRMS (Positive ion FAB) Calcd for C15H24NO3 [M+H]+ m/z 266.3605. Found: [M+H]+ m/z 266.1756.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:18]([O:22][N:23]1N=NC2C=CC=C[C:24]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C>[CH3:18][O:22][N:23]([CH3:24])[C:10]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH3:14])=[O:12]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
2-tert-Butoxycarbonylamino-butyric acid (500 mg, 2.46 mmol), HBTU (1.03 g, 2.71 mmol) and DIPEA (1.22 mL, 7.38 mmol) were dissolved in DMF (10 mL) and stirred for 30 min. N,O-dimethylhydroxylamine hydrochloride (360 mg, 3.69 mmol) was added and the reaction mixture was stirred for 1 h. The solvents were removed in vacuo and the residue was purified by column chromatography to give the title compound (380 mg, 63%) as a cream oil. LCMS (ES+): 269.2 [MNa]+.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[C:7]1(=[O:22])[C:20]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][C:8]1=[O:21].[NH4+].[Cl-]>C1COCC1>[CH2:1]([C:8]1([OH:21])[C:7]([CH2:1][CH2:2][CH2:3][CH3:4])([OH:22])[C:20]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Mg]Cl
Reactant: O=C1C=Cc2c(ccc3ccccc23)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCC1(O)c2ccccc2-c2ccccc2C1(O)CCCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
300 ml of a 2.0 M solution of n-butylmagnesium chloride (0.6 mol) were added dropwise to a solution of 41.75 g (0.2 mol) of phenanthrenequinone in 800 ml of dry THF at an internal temperature of 10° C. over a period of 1.5 hours and the mixture was subsequently stirred at RT for 6 hours. After hydrolysis with 125 ml of saturated NH4Cl solution, the precipitate was filtered off with suction, washed with ethyl acetate, the filtrate was extracted twice with Water and the organic phase was dried over Na2SO4. The brown solid which remained after evaporation of the solvent was subsequently recrystallized twice from EtOH/H2O (70:30). This gave 60.6 g (93%) of colorless needles.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([OH:27])=O)=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>>[CH3:35][N:36]([CH3:42])[CH:37]1[CH2:41][CH2:40][N:39]([C:25]([C:22]2[N:23]=[CH:24][C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[O:27])[CH2:38]1
Reactant: CN(C)C1CCNC1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CCC(N(C)C)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and 3-(dimethylamino)pyrrolidine (TCI, Cat. No. D1859). LCMS (M+H)+: m/z=556.3.