Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:23]2[N:24]=[N:25][NH:26][N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:44][CH2:45][N:46]1[C:50](=[O:51])[C:49]2=[CH:52][CH:53]=[CH:54][CH:55]=[C:48]2[C:47]1=[O:56].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:28][C:29]2[CH:30]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:32]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:34]=2)[C:23]2[N:24]=[N:25][N:26]([CH2:44][CH2:45][N:46]3[C:47](=[O:56])[C:48]4[C:49](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:51])[N:27]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2cc3c(cc21)COC3
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCN3C(=O)c4ccccc4C3=O)n2)c2cc3c(cc21)COC3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of (S)-9-[(3,5-bis-trifluoromethyl-benzyl)-(2H-tetrazol-5-yl)-amino]-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (Example 72, Step 6) (0.84 mmol) and N-(2-Hydroxyethyl)phthalimide (2.51 mmol) in dichloromethane (10 mL), add triphenylphosphine (2.51 mmol) followed by dropwise addition of diethylazodicarboxylate (2.51 mmol). After stirring at room temperature for 14 h, remove the solvent under vacuum. Chromatograph over silica gel eluting with ethyl acetate/hexane (5-50%) to provide the title compound as a colorless foam. MS (ES+): 772 (M+H).
Reaction SMILES: [OH:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:28]([O:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CC1=C[C@H]2CC(OC(=O)c3ccccc3)O[C@H]2C1
Temperature: 25 °C

Procedure:
Purified lactol 7 (591.5 mg, 3.84 mmol, 1 eq.), was dissolved in CH2Cl2 (7 ml) and stirred at r.t. Dimethylaminopyridine (23.5 mg, 0.19 mmol, 5 mol %) was added as a solid. Triethylamine (647.5 μl, 4.61 mmol, 1.2 eq.) and benzoyl chloride (534.5 μL, 4.61 mmol, 1.2 eq.) were added via syringe. The reaction mixture was stirred at r.t. for 36 h, filtered over basic alumina and the organic phase was concentrated to give the crude material. The material was purified by column chromatography eluting with petrol/EtOAc (3:1) to give the benzoyl acetal 55 (as an approximately 1.3:1 mixture of diasteroisomers, 706.7 mg, 71%) as pale yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:17][C:18](OCC)=[O:19])[C:12]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:11]=3[C:10]=2[CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]([CH2:17][CH2:18][OH:19])[C:12]3[CH2:23][CH2:24][N:25]([CH3:27])[CH2:26][C:11]=3[C:10]=2[CH:9]=1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCO)C1
Temperature: 100 °C
Yield: 1.5 %

Procedure:
To a solution of lithium aluminum hydride (0.059 g, 1.5 mmol) in THF (30 mL) was added ethyl 2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)acetate (0.4 g, 1.3 mmol) in THF (10 mL) drop wise at 0° C. The reaction mixture was further heated at 100° C. for 6 h. Reaction was monitored by TLC and LCMS. On completion of the reaction, reaction mixture was quenched with H2O:NaOH:H2O (1:1:3) and the contents were filtered. The filtrate obtained was extracted with Ethyl acetate. Combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain crude product (300 mg). 100 mg of the crude was purified by preparative TLC to obtain 5 mg of 2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanol as free base. The free base (0.015 g 0.056 mmol) was further dissolved in THF (2 mL), oxalic acid (0.007 g, 0.056 mmol) in THF (1 mL) was added to it and the resulting mixture was further stirred for 30 min at room temperature. The precipitate obtained was filtered and dried under vacuum to afford 20 mg of 2-(8-chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)ethanol as an oxalate salt. 1H NMR (CD3OD) 7.45 (s, 1H), 7.4 (d, 1H), 7.1 (d, 1H), 4.3 (s, 2H), 4.2 (t, 2H), 3.9 (t, 2H), 3.5 (t, 2H), 3.2 (t, 2H), 2.9 (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[F:14])([CH3:6])([CH3:5])[CH3:4].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][C:8]=1[F:14])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)COc1ccc(C(C)(C)C)c(F)c1
Yield: 83.2 %

Procedure:
Sixty % sodium hydride (128 mg, 3.2 mmol), 4-tert-butyl-3-fluorophenol (450 mg, 2.7 mmol), tert-butyl bromoacetate (632 mg, 3.2 mmol) were treated in the same procedure described in Example 3(b) to furnish 634 mg (82% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[CH:26]([NH:28][CH2:29][CH2:30][CH:31]1[O:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:27]>>[F:19][C:17]1[CH:16]=[C:15]([F:21])[CH:14]=[CH:13][C:18]=1[N:9]1[C:3]2[C:4](=[CH:5][C:6]([F:8])=[C:7]([N:33]3[CH2:34][CH2:35][O:36][CH:31]([CH2:30][CH2:29][NH:28][CH:26]=[O:27])[CH2:32]3)[C:2]=2[F:1])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: O=CNCCC1CNCCO1
Product: O=CNCCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c2F)CCO1

Procedure:
By the use of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2formylaminoethyl)morpholine, the reaction is similarly carried out as Example 26 to give 1-(2,4-difluorophenyl)-6,8-difluoro-7-[2-(2-formylaminoethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1.[H][H]>CO.O1CCCC1.[Pd]>[CH3:23][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1
Reactant: [H][H]
Reactant: CC(C)C=C(c1cccc(N(C)C)c1)c1cc2cccnc2[nH]1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(c1cccc(N(C)C)c1)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A solution of N,N-dimethyl-3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)benzenamine (1.6 g, 5.2 mmol) in methanol (40 mL) and tetrahydrofuran (40 mL) was treated with 10% palladium on carbon (320 mg). The reaction was stirred for 16 h at 25° C. under a balloon filled with hydrogen gas. At this time, the reaction mixture was filtered through a pad of celite and washed with tetrahydrofuran (2×20 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (30 g, petroleum ether/ethyl acetate 8:1) afforded N,N-dimethyl-3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)butyl)benzeneamine (1.2 g, 75%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 9.54 (br. s., 1H), 8.14 (d, 1H, J=4.5 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.2 Hz), 7.03 (dd, 1H, J1=7.8 Hz, J2=4.8 Hz), 6.64-6.57 (m, 3H), 6.30 (s, 1H), 4.12 (t, 1H, J=8.1 Hz), 2.89 (s, 6H), 2.09-1.81 (m, 2H), 1.61-1.52 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])(=O)[O:5]CC)[CH3:2].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[CH2:9]([P:4]([Cl:23])(=[O:5])[O:3][CH2:1][CH3:2])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCCCCCCCP(=O)(OCC)OCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: C=CCCCCCCCCCP(=O)(Cl)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10-undecenylphosphonic acid diethyl ester (53.51 g, 180 mmol) in CH2Cl2 (350 mL) was cooled to about −8° C. Oxalyl chloride (32 mL, 370 mmol, 2 eq.) was added slowly to the mixture, the mixture was warmed to room temperature and stirred overnight. Solvent was removed to dryness and the excess oxalyl chloride was azeotropically removed with hexane three times (100 mL). The mixture was dried in a vacuum oven at 40° C. overnight and the product was used without further purification.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)=[O:11])[CH:8]=[CH:9][C:2]=12.[H-].[Na+].[CH3:21]I>CN(C)C=O.O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([O:18][CH3:21])[CH2:14][CH2:13]3)=[O:11])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(c1ccc2nonc2c1)N1CCC(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2ccc3nonc3c2)CC1
Reaction time: 3 h
Yield: 30.3 %

Procedure:
1-(Benzofurazan-5-ylcarbonyl)-4-hydroxypiperidine (840 mg, 3.40 mmol) was dissolved in dimethylformamide (12 mL) and treated with 60% sodium hydride (150 mg, 3.75 mmol) for 30 minutes. Methyl iodide (650 mg, 4.54 mmol) was added, and, after 3 hours at room temperature, the reaction mixture was further treated with the same quantities of sodium hydride and methyl iodide as above and allowed to stand for 16 hr. The reaction solution was diluted with water and product was extracted into ethyl acetate. The organic solution was washed with water and saturated sodium chloride and dried over MgSO4. The crude product was purified by decolorization with charcoal in ethanol, twice chromatographed on silica gel by elution with hexane/ethyl acetate (2:1), and finally by kugelrohr distillation at 125-140° C. to yield 1-(benzofurazan-5-ylcarbonyl)-4-methoxypiperidine (269 mg, 30%) as a pale yellow oil. IR: 1639, 1440, 1274, 1101, and 1089 cm−1. 1H NMR (500 MHz): δ 7.91 (1H, dm, J=9.2 Hz), 7.85 (1H, t, J=1.1 Hz), 7.43 (1H, dd, J=9.2 and 1.2 Hz), 3.90-4.05 (1H, m), 3.55-3.72 (2H, m), 3.53 (1H, sept, J=3.5 Hz), 3.38 (3H, s), 3.20-3.35 (1H, m), 1.90-2.02 (1H, m), 1.65-1.85 (2H, m), and −1.65 ppm (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13]C(=O)C>C(O)C.[OH-].[K+]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH2:13]
Reactant: COc1cc(OC)c(Cl)c(NC(C)=O)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 44 h

Procedure:
To a solution of N-(2,6-dichloro-3,5-dimethoxy-phenyl)-acetamide (34.5 g, 264 mmol) in ethanol (1.3 L), 2M KOH (0.72 L) is added. Then, the reaction mixture is heated to reflux, stirred for 44 h at reflux, then allowed to cool to RT. The resulting suspension is cooled to 0° C. stirred for 1 h, and filtered. The residue is washed with a small portion of cold EtOH/H2O (1:1) and with cold H2O till neutrality, and dried to provide the title compound as a white solid: ESI-MS: 222.0/224.0 [MH]+, TLC: Rf=0.52 (Hex/EtOAc, 1:1).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[S:24][CH:23]=[CH:22][N:18]2[C:19](=[O:21])[CH:20]=1.[I:27]N1C(=O)CCC1=O>C(#N)C>[CH3:1][C:2]([CH3:26])([CH3:25])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[S:24][CH:23]=[CH:22][N:18]2[C:19](=[O:21])[C:20]=1[I:27]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC(C)(C)C
Solvent: CC#N
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC(C)(C)C

Procedure:
A solution of Step 1 intermediate (275 mg, 5.816 mmol) was treated with N-iodosuccinimide (143 g, 6.327 mmol) in acetonitrile (10 ml) according to the procedure described in Step 4 of Intermediate 2 to afford a crude product which was purified by column chromatography using 2% ethyl acetate in chloroform as eluent to afford 510 mg of the desired compound as a yellow solid; 1H NMR (300 MHz, DMSO-d6) 1.08 (s, 9H), 3.58 (m, 2H), 3.81 (m, 3H), 7.07-7.12 (m, 2H), 7.30-7.33 (m, 2H), 7.41-7.48 (m, 1H), 7.94-7.96 (m, 1H), 8.23-8.29 (m, 1H); ESI-MS (m/z) 497.21 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].N1(C2C=C[C:26]([CH:27]=[O:28])=CC=2)C=CC=N1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:17]=[CH:16][C:13](/[CH:14]=[CH:26]/[CH:27]=[O:28])=[CH:12][CH:11]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cn2)cc1
Product: O=C/C=C/c1ccc(-c2ccc([N+](=O)[O-])cn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-nitro-2-pyridinyl)benzaldehyde (prepared as described in Reference Example 19) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 255 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][C:17]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12]C1=O.CO[CH:31]([O:34][CH3:35])[O:32][CH3:33]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][C:17]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:31]1([O:32][CH3:33])[O:34][CH3:35]
Reactant: COC(OC)OC
Reactant: CCCCCC1(C=C[C@H]2CCC(=O)[C@@H]2CCCCCCC(=O)OC)OCCO1
Product: CCCCCC1(C=C[C@H]2CCC(OC)(OC)[C@@H]2CCCCCCC(=O)OC)OCCO1
Reaction time: 6 h

Procedure:
A mixture of 1.5 g of 9-oxo-15,15-ethylenedioxy-13-prostenoic acid methyl ester, 20 ml of trimethoxy-methane and 3 drops of concentrated H2SO3 is boiled for 6 hours. 15 ml of the solvent is distilled within 2 hours. The residue is diluted with 30 ml of diethyl ether, washed with aqueous saturated NaHCO3 solution and H2O and dried over MgSO4. The solvent is distilled. After chromatographic purification of the residue (silica gel/diisopropyl ether), 9,9-dimethoxy-15,15-ethylenedioxy-13-prostenoic acid methyl ester is obtained.
Reaction SMILES: [CH:1]1([N:4](CC2C=CC(OC)=CC=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:51])=[C:32]([CH:38]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:51][C:31]1[C:32]([CH:38]2[CH2:39][CH2:40][NH:41][CH2:42][CH2:43]2)=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:30]=1[NH:29][C:7]1[N:6]=[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)[C:10]2=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]2[N:8]=1
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C#N)cc(N)c2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(C2CCNCC2)c1
Temperature: 70 °C

Procedure:
A mixture of 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (142 mg, 0.357 mmol), tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)piperidine-1-carboxylate (100 mg, 0.298 mmol) and Cs2CO3 (194 mg, 0.596 mmol) in DMF (3 mL) was heated at 70° C. for 2 h. This was diluted with EtOAc, washed with water and brine and dried over Na2SO4. The crude mixture containing 2-((2-chloro-5-cyano-3-(piperidin-4-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile was carried forward to next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1.[H-].[Na+].[CH3:30]I.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:17]([C:23]2[CH:24]=[N:25][N:26]([CH3:30])[CH:27]=2)=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3-c3cn[nH]c3)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cnn(C)c3)c2cc1OC
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
6,7-Dimethoxy-4-[6-methyl-2-(1H-pyrazol-4-yl)-pyridin-3-yloxy]-quinoline (compound 434) (30 mg) was suspended in N,N-dimethylformamide (1 ml), 60% sodium hydride (9.9 mg) was added to the suspension, and the mixture was then stirred for 30 min. Methyl iodide (18 mg) was added to the reaction solution, and the mixture was stirred for one hr. Water was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (23 mg, yield 73%).
Reaction SMILES: [CH3:1][CH:2]([CH:9]=[C:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:3]C(OCC)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].CC[O:27]CC>>[CH3:1][CH:2]([CH:9]=[C:10]=[C:11]([CH3:18])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[CH2:3][OH:27]
Reactant: CCOC(=O)CC(C)C=C=C(C)CCC=C(C)C
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(=C=CC(C)CO)CCC=C(C)C
Reaction time: 22 h
Yield: 77 %

Procedure:
A solution of 25 mM of the ester obtained according to letter (i) above in 13 ml of anhydrous ether was added under stirring to a solution of 0.66 (17.5 mM) of LiAlH4 in 35 ml of anhydrous ether. Stirring was carried on at room temperature for 22 h, whereupon the reaction mixture was poured onto ice. After acidification with a 10% aqueous HCl solution, extraction with ether, washing with water and drying, followed by evaporation and distillation there was obtained a fraction having b.p. 130°-7°/12 Torr (yield 77%) containing 90-95% of the desired allenic alcohol in the form of a diastereoisomeric mixture.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1ccc(Cn2c(C(=O)OC)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.3 %

Procedure:
To a mixture of 6-bromo-2-(4-methoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (2.00 g) in methanol (10 ml) and tetrahydrofuran (20 ml) was added 8N aqueous sodium hydroxide solution (1 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and water was added. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from methanol to give the title compound (1.29 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10](=[O:20])[CH2:9]2)=[CH:4][C:3]=1[F:21].[Li+].[OH-:23].Cl>C1COCC1.O>[C:16]([O:15][C:13]([NH:11][CH2:12][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:21])[CH:4]=1)[CH2:9][C:10]([OH:23])=[O:20])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(Cl)c(F)c2)CC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@@H](CC(=O)O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 92 (912 mg, 2.91 mmol) in THF/H2O (2:1; 15 mL) was added solid LiOH (209 mg, 8.72 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mixture was acidified with 1M HCl to ca. pH 2-3 then twice extracted with EtOAc. The combined EtOAc layers were dried (Na2SO4), filtered and concentrated to afford 902 mg (93.5%) of (S)-4-(tert-butoxycarbonylamino)-3-(4-chloro-3-fluorophenyl)butanoic acid (100) which was used without further purification.
Reaction SMILES: [Br:1][CH:2]1[CH:7]([Br:8])[CH2:6][CH:5]([OH:9])[CH:4]([OH:10])[CH2:3]1.CO[C:13](OC)([CH3:15])[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:1][CH:2]1[CH:7]([Br:8])[CH2:6][CH:5]2[O:9][C:13]([CH3:15])([CH3:14])[O:10][CH:4]2[CH2:3]1
Reactant: OC1CC(Br)C(Br)CC1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)OC2CC(Br)C(Br)CC2O1
Reaction time: 3 h

Procedure:
The compound obtained in Step (10) (20.6 g, 75.62 mmol) was placed in a reaction vessel, and air in the vessel was replaced with nitrogen. 2,2-dimethoxypropane (12.92 ml) and p-toluenesulfonic acid (0.9 g) were added to the vessel, and the mixture was stirred for 3 hours. After the completion of the reaction had been confirmed, the mixture was filtrated through activated alumina, and the filtrate was concentrated under reduced pressure, whereby 5,6-dibromo-2,2-dimethylhexahydro-1,3-benzodioxol was obtained (17.1 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([O-:19])=[O:18].[Na+].[NH2:21][C:22]1[C:39]([CH2:40][N:41]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH3:43])=[CH:38][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33]Cl)=[O:27])=[CH:24][C:23]=1[Br:50]>>[NH2:21][C:22]1[C:39]([CH2:40][N:41]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH3:43])=[CH:38][C:25]([C:26]([O:28][CH2:29][CH2:30][N:31]([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][O:18][C:17](=[O:19])[CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[O:27])=[CH:24][C:23]=1[Br:50]
Reactant: CCCN(CCCl)CCOC(=O)c1cc(Br)c(N)c(CN(CC)C2CCCCC2)c1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: CCCN(CCOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)CCOC(=O)c1cc(Br)c(N)c(CN(CC)C2CCCCC2)c1

Procedure:
This compound was prepared from sodium 2-[(2,6-dichlorophenyl)-amino]-phenyl-acetate and N-{2-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyloxy]-ethyl}N-(2-chloroethyl)-n-propylamine analogous to Example 8. Oil.