Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([C:13]1[CH:18]=[CH:17][N:16]=[N:15][CH:14]=1)=O)(=[O:3])[NH2:2].C[O-].[Na+]>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:2][C:1](=[O:3])[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:14][N:15]=1
Reactant: NC(=O)c1ccccc1NC(=O)c1ccnnc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(-c2ccnnc2)nc2ccccc12
Temperature: 110 °C
Yield: 31.7 %

Procedure:
A 100 mL round-bottom flask equipped with a Dean-Stark trap was charged with a mixture of N-(2-carbamoylphenyl)pyridazine-4-carboxamide (300 mg, 1.0 eq.), sodium methoxide (401 mg, 7.4 mmol, 6.0 eq.) and 10 mL of anhydrous toluene. The reaction mixture was heated to 110° C. and refluxed overnight. After cooling, the volatiles were removed in vacuo and the residue was quenched with a saturated aqueous solution of NH4Cl (10 mL). The pH of the mixture was adjusted to 3 with 10% HCl in water. The solution was extracted with DCM (50 ml×3). The combined organic layers were washed with brine, dried over Na2SO4. After filtration and evaporation, 88 mg of a yellow solid was obtained, LCMS m/z=225.1 (M+1) (Method A) (retention time=1.10 min) which was used in the next step without further purification.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].C(O)(=O)[CH2:8][CH2:9][C:10](O)=[O:11]>>[CH3:4][C@H:2]1[O:3][C:10](=[O:11])[C@H:9]([CH3:8])[O:6][C:1]1=[O:5]
Reactant: O=C(O)CCC(=O)O
Reactant: CC(O)C(=O)O
Product: C[C@@H]1OC(=O)[C@@H](C)OC1=O

Procedure:
Succinic anhydride is often a significant component of the intermediate-boiling impurities. Succinic anhydride can be separated from meso-lactide by washing the meso-lactide stream with a weakly basic aqueous phase. A suitable pH of the washing solution is in the range of from about 7.2 to about 11. This is believed to hydrolyze the succinic anhydride to form succinic acid. Some of the lactide may also be hydrolyzed to form mainly linear oligomers and possibly some lactic acid. The succinic acid is much more soluble in the basic aqueous phase than in the lactide phase, and will partition to the aqueous phase. The aqueous and organic phases are then separated to form a washed meso-lactide stream having a reduced level of succinic anhydride and perhaps other intermediate-boiling impurities. The washed meso-lactide stream can be recycled as described before.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[C:7]2[CH3:12].[Cl:14]P(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:14][C:3]1[C:2]([Cl:1])=[C:11]2[C:6]([C:7]([CH3:12])=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cncc2c(Cl)c(O)ccc12
Product: Cc1cncc2c(Cl)c(Cl)ccc12
Reaction time: 4 h

Procedure:
8-Chloro-7-hydroxy-4-methylisoquinoline (0.04 mole) and dichlorotriphenylphosphorane (0.04 mole) are heated to 240° C. under a nitrogen atmosphere. After 4 hours, the mixture is allowed to cool and is partitioned between chloroform and concentrated hydrochloric acid. The acidic extract is washed with chloroform, basified and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated to yield 7,8-dichloro-4-methylisoquinoline. The product is purified by chromatography on silica gel eluted with chloroform and finally by precipitation of the hydrochloride from ethanol-ether.
Reaction SMILES: C([O:5][P:6]([O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:31][C:32]3[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][N:35]=[C:34]([NH:42][C:43]4[CH:57]=[CH:56][C:46]([CH2:47][P:48](=[O:55])([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])=[CH:45][C:44]=4[O:58][CH3:59])[N:33]=3)=[C:24]3[C:28]=2[CH2:27][N:26]([CH3:29])[C:25]3=[O:30])[CH2:16][CH2:15]1)([O:8]C(C)(C)C)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[CH3:59][O:58][C:44]1[CH:45]=[C:46]([CH:56]=[CH:57][C:43]=1[NH:42][C:34]1[N:33]=[C:32]([NH:31][C:23]2[CH:22]=[CH:21][C:20]([C@H:17]3[CH2:16][CH2:15][C@H:14]([O:13][P:6]([OH:7])([OH:8])=[O:5])[CH2:19][CH2:18]3)=[C:28]3[C:24]=2[C:25](=[O:30])[N:26]([CH3:29])[CH2:27]3)[C:37]([C:38]([F:40])([F:41])[F:39])=[CH:36][N:35]=1)[CH2:47][P:48](=[O:55])([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OP(=O)(OC(C)(C)C)OC(C)(C)C)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](OP(=O)(O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diethyl [4-({4-[(7-{trans-4-[(di-tert-butoxyphosphoryl)oxy]cyclohexyl}-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino]-5-(trifluoromethyl)pyrimidin-2-yl]amino)-3-methoxybenzyl]phosphonate (Compound 228A, 38.5 mg, 0.044 mmol) in THF (2 mL) was added TFA (1 mL). The reaction mixture was stirred at rt for 1 h. Solvents were then removed in vacuo and the residue was purified by MDP (formic acid conditions) to obtain 31.9 mg of the desired product (yield: 95%). 1H NMR (DMSO-d6, 400 MHz): δ=1.19 (t, J=7.6 Hz, 6 H), 1.41-1.46 (m, 2 H), 1.66-1.76 (m, 4 H), 2.12-2.15 (m, 2 H), 2.49 (m, 1 H), 3.04 (s, 3 H), 3.29 (d, J=21.20 Hz, 2 H), 3.73 (s, 3 H), 3.96-4.03 (m, 4 H), 4.12 (m, 1 H), 4.47 (s, 2 H), 6.89 (d, J=7.6 Hz, 1 H), 7.05 (s, 1 H), 7.36 (d, J=8.8 Hz, 1 H), 7.43 (s, br, 1 H), 8.36 (d, J=0.8 Hz, 1 H), 8.98 (s, 1 H), 10.54 (s, 1 H). MS (ES+): m/z 758.21 [MH+]. HPLC: tR=1.27 min (UPLC TOF, polar—3 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][C:10]2=[O:12]
Reactant: O=C(O)CCc1ccccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Product: O=C1CCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
128.2 g (0.559 mol) of 3-(2-Bromo-phenyl)-propionic acid are placed in a 2-neck round bottom flask with gas outlet and stirrer. 133.2 g (1.12 mol) of thionyl chloride are added and the mixture is heated under reflux for 2 h with stirring in an argon atmosphere and excess thionyl chloride is removed in a vacuum. The resulting yellow oil is dissolved in 700 ml of methylene chloride, cooled to 0° C. and 82.0 g (0.615 mol) anhydrous aluminium chloride are added in small portions. The reaction mixture is stirred at 0° C. for 2 h and then hydrolyzed by carefully pouring it on crushed ice. The organic layer is separated. The aqueous layer is acidified with concentrated hydrochloric acid and extracted twice with methylene chloride. The combined organic layers are washed once with 2 M HCl, once with water, dried over anhydrous magnesium sulphate and the solvent is removed under reduced pressure (110.0 g, 87%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:11](=[O:13])[N:12]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[OH:40][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([CH:14]=[C:10]3[S:9][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[N:12][C:11]3=[O:13])=[CH:20][CH:19]=2)[CH2:26][CH2:25]1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(=O)CC4)cc3)S2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc(N4CCC(NC[C@H](O)COc5ccc(O)cc5)CC4)cc3)S2)CC1

Procedure:
The title compound was prepared from 1-{4-[2-(4-methyl-piperazin-1-yl)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 29) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>210C (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.24 (s, 3 H), 2.40-4.00 (m, 18 H), 6.64(d, J=8.9 Hz, 2 H), 6.73 (d, J=8.9 Hz, 2 H), 7.00(d, J=8.9 Hz, 2 H), 7.45(d, J=8.9 Hz, 2 H), 7.52 (s, 1 H), 8.89(brs, 1 H); MS (ES) m/z: 276.6 ((M+2H)2+, 100%); 552.0(MH+, 10%); HRMS Calcd. for C29H38N5O4S (MH+): 552.2645. Found: 552.2634.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[CH3:2][CH:3]1[CH2:8][CH2:7][NH:6][CH:5]([C:9]([O:11][CH2:16][CH3:17])=[O:10])[CH2:4]1
Reactant: CC1CCNC(C(=O)O)C1
Reactant: CCO
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CC(C)CCN1
Yield: 60 %

Procedure:
A solution of 13 g (0.072 mole) of 4-methyl-2-piperidine-carboxylic acid hydrochloride and 50 ml of thionyl chloride in 300 ml of ethanol was refluxed for 4 hours. At the end of this period, the solvent was evaporated under reduced pressure, and the residue was extracted with a solution of chloroform and saturated potassium carbonate solution. The chloroform layer was dried over anhydrous sodium sulfate and then chloroform was evaporated. Distillation of the residue gave 7.4 g (60%) of ethyl 4-methyl-2-piperidinecarboxylate, B.P. 76°-77° C/3 mmHg.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[F:11])[C:3]=1[C:4]#[N:5]
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1c(F)cccc1Br
Product: N#Cc1c(F)cccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
2-Bromo-6-fluorobenzonitrile and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane were coupled following the procedure in Example 2 to afford 3,2′-difluoro-5′-nitrobiphenyl-2-carbonitrile as a black solid: δH (360 MHz, CDCl3) 7.32-7.44 (3H, m), 7.71-7.77 (1H, m), 8.35-8.41 (2H, m).
Reaction SMILES: C([N:8]1[C:31]([CH3:33])([CH3:32])[CH2:30][O:29][C:10]2([CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:33][C:31]1([CH3:32])[CH2:30][O:29][C:10]2([CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH3:28])[CH:19]=3)=[O:17])[CH2:14][CH2:15]2)[CH2:9][NH:8]1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)C(C)(C)CO3)ccc1OC(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(C(=O)N2CCC3(CC2)CNC(C)(C)CO3)ccc1OC(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 100.9 %

Procedure:
To a solution of (8-benzyl-9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (51 mg, 0.11 mmol) in ethanol (2 mL) was added Pd(OH)2 (16 mg, 0.11 mmol) followed by ammonium formate (29 mg, 0.45 mmol). The reaction mixture was stirred at 40° C. for 18 h, then filtered and concentrated in vacuo to afford (9,9-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (40 mg, 98%). ESI-MS m/z calc. 360.5. found 361.3 (M+1)+; Retention time: 1.29 minutes (3 min run).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH3:13])[C:6]=1[CH2:14][N:15]([CH2:26][C:27]([O:29][CH3:30])=[O:28])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO>[CH3:30][O:29][C:27]([C:26]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:14][N:15]=1)[N:7]([CH3:13])[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:28]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1C)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
5-Bromo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (292 mg, 0.58 mmol) was dissolved in 10 mL of MeOH and placed in ice bath. NaOMe solution (0.4 mL, 1.75 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 0.1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 150 mg of the title compound as an off-white solid. MS: (+) m/z 313.13, 315.14 (M+1, 79/81Br).
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)[NH2:2].[CH2:10]([O:12][C:13](=[O:25])[C:14](=O)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O)[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:1]([C:3]2[CH:8]=[N:7][C:6]([CH3:9])=[CH:5][CH:4]=2)[N:2]=1)=[O:25])[CH3:11]
Reactant: Cc1ccc(NN)cn1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccn1
Product: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(C)nc2)n1

Procedure:
The general procedure of Referential Example 3-2) was repeated through use of the 5-hydrazino-2-methylpyridine (1.20 g) prepared in Referential Example 63 and the 4-(2-pyridyl)-2,4-dioxobutanoic acid ethyl ester (3.48 g) prepared in Referential Example 31, to thereby give the title compound as an oily product (0.459 g, 15%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(O)c2cc(Br)ccc2sc1=O
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)c1c(O)c2cc(-c3ccc(OC)cc3)ccc2sc1=O

Procedure:
4-Hydroxy-6-(4-methoxy-phenyl)-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 6-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester under conditions analogous to Example 7(a) using 4-methoxy-phenylboronic acid. 1H NMR (200 MHz, CDCl3): δ (ppm)=8.521 (s, 1H), 7.803-7.352 (m, 5H), 7.001 (s, 1H), 4.022 (s, 3H), 3.864 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.FC(F)(F)C1C=C(C(F)(F)F)C=CC=1CN1C2C(=CC(C=C3S[C:50]([N:52]4[CH2:57][CH2:56][NH:55][C@@H:54]([C:58](NC)=[O:59])[CH2:53]4)=NC3=O)=CC=2)C=N1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:55]5[CH2:56][CH2:57][N:52]([CH3:50])[CH2:53][C@@H:54]5[CH2:58][OH:59])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CNC(=O)[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)[C@@H](CO)C1

Procedure:
5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R) (4-Methyl-piperazin-2-yl)-methanol following General Procedure C.
Reaction SMILES: [Cl-].[Si]([O:9][C:10]1[CH2:11][CH2:12][C:13]2([C:25]([F:28])([F:27])[F:26])[CH:17]([CH:18]=1)[N+:16]([CH3:20])([CH3:19])[C:15]1[CH:21]=[CH:22][CH:23]=[N:24][C:14]2=1)(C(C)(C)C)(C)C.Cl>O1CCCC1>[CH3:19][N:16]([CH3:20])[C:15]1[C:14]([C:13]2([C:25]([F:28])([F:26])[F:27])[CH2:17][CH2:18][C:10](=[O:9])[CH:11]=[CH:12]2)=[N:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OC1=CC2C(C(F)(F)F)(CC1)c1ncccc1[N+]2(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)c1cccnc1C1(C(F)(F)F)C=CC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A solution of Example 26A (418 mg, 2.014 mmol) and (E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine (Aldrich, 527 mg, 2.316 mmol) in toluene (1.5 mL) was heated in a microwave at 140° C. for 2 hours, and then chromatographed on silica gel (AnaLogix SF15-24G; 50 micron silica; elution with 0-50% ethyl acetate in hexane at 20 mL/min). Repeated the reaction in a microwave at 120° C. for 2 hours with a solution of Example 26A (422 mg, 2.033 mmol) and (E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine (693 mg, 3.05 mmol) in toluene (2 mL), and then chromatographed on silica gel (AnaLogix® SF15-24G; 50 micron silica; elution with 0-50% ethyl acetate in hexane at 20 mL/min). The title compound (165 mg, 0.580 mmol) was isolated as an orange solid. A solution of the isolated intermediate 7-(tert-butyldimethylsilyloxy)-5,5-dimethyl-9a-(trifluoromethyl)-5a,8,9,9a-tetrahydro-5H-pyrido[3,2-b]indol-5-ium chloride (395 mg, 0.908 mmol) in tetrahydrofuran (9 mL) was treated with 1N hydrochloric acid (3.0 mL, 3.0 mmol). The reaction mixture was stirred overnight at ambient temperature, quenched with sodium bicarbonate solution (40 mL), extracted twice with ethyl acetate (40 mL), washed with brine, dried (Na2SO4), and concentrated to an orange oil. The residue was purified by silica gel chromatography (AnaLogix® SF 10-8G; 50 micron silica; elution with 0-40% ethyl acetate in hexane at 15 mL/min) to provide additional title compound (131 mg, 0.461 mmol) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ ppm 8.54 (dd, J=4.5, 1.6, 1H), 7.75 (dd, J=8.0, 1.7, 1H), 7.74 (dd, J=10.2, 2.1, 1H), 7.35 (dd, J=8.1, 4.5, 1H), 5.90 (d, J=10.2, 1H), 3.54-3.44 (m, 1H), 2.65 (s, 3H), 2.45-2.35 (m, 2H), 2.33 (s, 3H), 2.13-1.97 (m, 1H); MS (DCI/NH3) m/e 285 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:21]#[N:22].[Cl-].[Ca+2].[Cl-].O.N>S([O-])([O-])(=O)=O.[Cu+2].O>[C:21]([C:2]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:11]=3[S:12][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:22]
Reactant: N#C[Cu]C#N
Reactant: CCOc1ccc2c(c1)CCc1c(Cl)cccc1S2
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCOc1ccc2c(c1)CCc1c(C#N)cccc1S2
Reaction time: 15 h

Procedure:
The mixture of 520mg of 9-chloro-10,11-dihydro-2-ethoxydibenzo-[b,f]thiepin, 0.1g of copper sulfate, 1g of copper cyanide and 20ml of N-methylpyrrodlidone was refluxed with stirring for 15hrs., while preventing the moisture with calcium chloride. After cooling, to this was added 20ml of conc. ammonia water and 100ml of water, and the mixture was extracted. The extract was washed with water, dried over anhydrous potassium carbonate and, the solvent was evaporated to obtain the residue. This was chromatographed on silica gel, eluted with the mixed solvent of benzene and n-hexane (4:1) and there was otained 150mg of 9-cyano-10,11-dihydro-2-ethoxydibenzo[b,f]thiepin having a melting point of 124°to 126° C as colorless powdered crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].C(OC(=O)[C@H](CC1C=CC=CC=1)N)(C)(C)C>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2ccccc2c1Cl
Agent: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1sc2ccccc2c1Cl

Procedure:
Following the 11a synthetic method, using B1 (110.65 mg, 0.5 mmol) instead of A1 gave 11b as a colorless oil; (164.98 mg, 91.7%). [α]D25: +23.3 (c=0.42, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 8.06-8.00 (m, 1H), 7.91-7.87 (m, 1H), 7.80 (d, J=6.9 Hz, 1H), 7.62-7.55 (m, 2H), 7.37-7.22 (m, 5H), 5.05-4.98 (m, 1H), 3.45-3.26 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.56, 159.74, 137.75, 136.74, 136.67, 132.78, 129.51, 128.40, 127.67, 126.88, 125.74, 123.03, 122.83, 118.86, 54.09, 36.83; HRMS (ESI): calcd for: C18H14ClNO3S [M−H]−=358.0310, obsd [M−H]−=358.0312.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=2)[NH2:35])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:24][C:12]1[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)[CH:33]=3)=[O:23])=[CH:19][CH:20]=2)=[CH:14][C:9]([NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])=[CH:10][CH:11]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)Nc2cccc(N3CCN(C)CC3)c2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 3-(4-methylpiperazin-1-yl)aniline (29.8 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum N-(6-methyl-4′-{[3-(4-methylpiperazin-1-yl)anilino]carbonyl}-1,1′-biphenyl-3-yl)-3-furamide (59.5 mg, 77%). NMR; δH [2H6]-DMSO 10.13,(1H, s), 9.93,(1H, s), 8.36,(1H, s), 8.02,(2H, d), 7.78,(1H, t), 7.68,(1H, dd), 7.63,(1H, d), 7.51,(2H, d), 7.43,(1H, m), 7.30-7.26,(2H, m), 7.17,(1H, t), 6.99,(1H, m), 6.70,(1H, dd), 3.12,(4H, m), 2.46,(4H, m), 2.22,(6H, s). LCMS: retention time 2.43 min, MH+495.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.C[Si]([C:15]#[N:16])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([C:15]#[N:16])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: [O-][n+]1cccc(C2CC2)c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ncccc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.47 g of 3-cyclopropylpyridine-1-oxide [121-1] was dissolved in 15 mL of chloroform, and 1.89 mL of trimethylsilyl cyanide was added thereto. Subsequently, a solution prepared by dissolving 1.3 mL of dimethylcarbamoyl chloride in 5 mL of chloroform was added dropwise over 30 minutes, and was stirred overnight at room temperature. Thereto, 10 mL of 10% aqueous solution of potassium carbonate was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered and the filtrate was concentrated under reduced pressure, to obtain a residue. The residue was purified by silica gel column chromatography, and 680 mg of 3-cyclopropylpyridine-2-carbonitrile [121-2] was obtained as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10].C(=O)(O)[O-].[Na+]>CCO.[Fe]>[Cl:2][C:3]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)cc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 100 mL of conc. aqueous HCl in 100 mL EtOH was added dropwise to a suspension of 20.00 g (358 mmol) of iron powder and 20 g (73.33 mmol) of [2-(2-chloro-4-nitro-phenoxy)-ethyl]-diethyl-amine in 200 mL EtOH, while the temperature was kept below 20° C. by cooling with ice. The reaction mixture was stirred for 30 minutes, neutralised with 10% aqueous sodium bicarbonate solution and was exhaustively extracted with EtOAc. The combined org. extracts were dried over magnesium sulphate and evaporated down i. vac. The product was stored under a nitrogen atmosphere.