Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCc1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Brc1cnc2ccc(NCc3ccccn3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-(aminomethyl)pyridine according to general procedure 1 providing the amino compound (97 mg, 25%) as a white solid; Rf=0.80 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.52-8.51 (m, 1H), 7.83-7.79 (m, 1H), 7.63 (d, J=9.7 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.41 (s, 1H), 7.33-7.31 (m, 1H), 6.84 (d, J=9.7 Hz, 1H), 4.70 (s, 2H); ES-MS: (M+H)=304, 306 m/z.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=2)[N:20]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]([F:25])([F:27])[F:26])=[N:22][N:23]=3)[N:20]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Cc1ccccc1N1CCNCC1
Product: Cc1ccccc1N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
A mixture of 1-(2-methylphenyl)piperazine and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2-methylphenyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20]([C:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)=[O:21])[CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCCc2ccc(NC(=O)c3c[nH]c4ccccc4c3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of [7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acid tert-butyl ester (273) (250 mg, 0.6 mmol) in dichloromethane (2 mL) was added TFA (2 mL). The reaction was stirred at room temperature for 30 min. More dichloromethane (10 mL) was added to the reaction mixture and the solution was washed with sat. NaHCO3 solution (5 mL). A precipitate began to form in the organic layer so the combined organic layers were concentrated to yield N-(1-aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (273-I) (185 mg, 93%). HPLC ret. time 1.94 min, 10-99% CH3CN, 5 min run; ESI-MS 334.5 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][N:14]=1)(=[O:12])=[O:11].Br[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([CH2:23][C:24]([OH:26])=[O:25])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:12])=[O:11])=[N:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(C(C)C)cn1
Reactant: CC(C)(C)OC(=O)CBr
Product: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of 5-isopropyl-pyridine-2-sulfonic acid (2-methoxy-phenyl)-amide with tert-butyl bromoacetate
Reaction SMILES: Cl[CH:2]1[NH+:11]2[CH2:12][CH2:13][C:14]3[C:19]([C:10]2=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([O:23][CH3:24])=[C:4]([O:25][CH3:26])[C:3]1=2)=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=3.[Cl-]>O1CCCC1>[CH3:26][O:25][C:4]1[C:3]2[C:2]3([CH2:7][CH2:8][CH2:3][CH2:2]3)[N:11]3[CH2:12][CH2:13][C:14]4[C:19]([C:10]3=[CH:9][C:8]=2[CH:7]=[CH:6][C:5]=1[O:23][CH3:24])=[CH:18][C:17]1[O:20][CH2:21][O:22][C:16]=1[CH:15]=4
Reactant: COc1ccc2c(c1OC)C(Cl)[NH+]1CCc3cc4c(cc3C1=C2)OCO4
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)C1(CCCC1)N1CCc3cc4c(cc3C1=C2)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a suspension of 8-chloro-9,10-dimethoxy-5,6-dihydro-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinolin-7-ylium; chloride (1.34 g, 3.3 mmol) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added butyl-1,4-dimagnesium bromide solution (3 M in tetrahydrofuran, 17.4 mL, 4.95 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (30 mL). The mixture was extracted with diethyl ether (2×100 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from methanol to afford 9′,10′-dimethoxy-5′,6′-dihydrospiro[cyclopentane-1,8′-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline] (120 mg, 10%). LC/MS m/e calcd for C24H25NO4 (M+H)+: 392.47, observed: 392.2; 1H NMR (400 MHz, Chloroform-d) δ ppm 1.84-1.97 (m, 2 H) 1.97-2.09 (m, 2 H) 2.18-2.30 (m, 2 H) 2.37-2.49 (m, 2 H) 2.82 (t, J=5.56 Hz, 2 H) 3.31 (t, J=5.56 Hz, 2 H) 3.85 (s, 3 H) 3.88 (s, 3 H) 5.73 (s, 1 H) 5.95 (s, 2 H) 6.58 (s, 1 H) 6.64 (d, J=8.34 Hz, 1 H) 6.75 (d, J=8.34 Hz, 1 H) 7.16 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:32]C(=O)OC(C)(C)C)[C:12]1[N:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[C:16](=[O:26])[C:15]2=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][N:14]2[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>>[NH2:32][C@H:11]([C:12]1[N:17]([C:18]2[CH:19]=[C:20]([F:25])[CH:21]=[C:22]([F:24])[CH:23]=2)[C:16](=[O:26])[C:15]2=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][N:14]2[N:13]=1)[CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)c1nn2ccc(C#N)c2c(=O)n1-c1cc(F)cc(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccn2nc([C@@H](N)CCOCc3ccccc3)n(-c3cc(F)cc(F)c3)c(=O)c12
Yield: 107.2 %

Procedure:
(S)-tert-Butyl (3-(benzyloxy)-1-(5-cyano-3-(3,5-difluorophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)propyl)carbamate (50 mg, 0.09 mmol) was treated with a solution of hydrochloric acid in dioxane (4M, 350 μl, 1.4 mmol) according to the method described in Preparation 1 to obtain 42 mg (92% yield) of the title compound as a yellow solid. Purity 96%.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH:12][NH2:13]>C(O)C>[CH3:11][N:12]1[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][CH:1]=[N:13]1
Reactant: CNN
Reactant: O=CC=Cc1ccccc1
Solvent: CCO
Product: CN1N=CCC1c1ccccc1
Yield: 22.5 %

Procedure:
Cinnamaldehyde (13.2 g) was added dropwise to a solution of 5 g methylhydrazine in 50 ml ethanol, and the mixture was heated under reflux for six hours. At the end of reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 50 ml ether. The solution was washed with water and concentrated, and the concentrate was distilled under reduced pressure, giving 3.6 g (yield: 22%) of pure product. B.p.: 95°-105° C./5 mmHg; NMR (CDCl3): 2.2-3.3 (2H, m), 2.65 (3H, s), 3.76 (1H, dd, J=10, 14 Hz), 6.51 (1H, t, J=2 Hz ], 7.1-7.6 (5H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>ClCCl>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:16][CH2:15]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 20.0 g 4-nitrobenzoylchloride in 100 ml dichloromethane is added dropwise to a solution of 12.0 ml of N-methylpiperazine and 30 ml of triethylamine in 600 ml of dichloromethane at ambient temperature. The reaction solution is stirred for one hour, then washed three times with water, dried with sodium sulphate and evaporated to dryness. The residue is stirred with tert-butylmethylether and dried at 40° C.
Reaction SMILES: C(NCC)C.O.[CH2:7]([O:9][C:10](=[O:30])[CH:11]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)[C:12](O)=O)[CH3:8].C=O>C(Cl)Cl>[CH2:7]([O:9][C:10](=[O:30])[C:11]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)=[CH2:12])[CH3:8]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)O
Agent: C=O
Solvent: CCNCC
Solvent: O
Solvent: ClCCl
Product: C=C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
Diethylamine (0.29 g, 3.00 mmol), water (2 mL) and methylene chloride (2 mL) was added to a mixture of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.00 g, 2.96 mmol) and 37% aq. solution of formaldehyde (0.25 g, 3.05 mmol) at 0° C. The mixture was stirred for 16 h at room temperature and then poured onto ice-water and extracted with methylene chloride. The organic layer was washed with 5% NaHCO3 and dried. Filtration and concentration under reduced pressure gave 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.75 g, 83%).
Reaction SMILES: CN1CCCN(C)C1=O.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[CH2:18][S:19]([C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=1)(=[O:21])=[O:20].C([Li])CCC.[I:34]N1C(=O)CCC1=O>C1COCC1>[F:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[C:12]=1[CH:18]([I:34])[S:19]([C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[O:24][N:23]=1)(=[O:20])=[O:21]
Reactant: O=C1CCC(=O)N1I
Reactant: CC1(C)CC(S(=O)(=O)Cc2c(F)cccc2F)=NO1
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CC1(C)CC(S(=O)(=O)C(I)c2c(F)cccc2F)=NO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU) (0.10 ml, 0.83 mmol) and 3-(2,6-difluoro-phenylmethanesulfonyl)-5,5-dimethyl-4,5-dihydro-isoxazole (0.20 g, 0.69 mmol) were dissolved under nitrogen in THF (7 ml) and cooled to −78° C. n-Butyl lithium (2.5M in hexane) (0.33 ml, 0.83 mmol) was added dropwise. After 30 min at −78° C., N-iodosuccinimide (NIS) (187 mg, 0.83 mmol) was added. The mixture was stirred for 1 hour and allowed to warm slowly to room temperature. The reaction was quenched by addition of aqueous ammonium chloride solution. Extraction was carried out several times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) and recrystallised from isopropyl alcohol to give the product (Compound No. 1.25 of Table 27) as a white solid (110 mg, 38% yield).
Reaction SMILES: C(N(CC)[C:4](=[O:29])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:28])[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH3:18])C.[OH-].[K+].C([OH:36])C.C(O)(=O)C>O>[OH:28][C@H:21]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH2:20][NH:19][C@H:17]([CH3:18])[CH2:16][C:12]1[C:11]2[C:15](=[C:7]([O:6][CH2:5][C:4]([OH:29])=[O:36])[CH:8]=[CH:9][CH:10]=2)[NH:14][CH:13]=1
Reactant: CCO
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3cccnc3)c[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1cccnc1

Procedure:
A solution of N,N-diethyl-2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetamide (30 mg, 0.071 mmol) and potassium hydroxide (120 mg, 2.1 mmol) in water (1 mL)/ethanol (1 mL) is stirred at 60° C. for 6 hours. After cooling, to the mixture is added acetic acid (0.112 mL), and the mixture is concentrated. The residue is purified by preparative reversed phase HPLC (octadecylsilyl, trade name: Combiprep, ODS-A (YMC), inner diameter: 50×20 mm, particle size: 5 μm, pore size: 120 angstrom (hereinafter, this column is used in preparative reversed phase HPLC column), 0.05% trifluoroacetic acid/water-0.035% trifluoroacetic acid/acetonitrile) to give the desired {3-[(2R)-2-((2R)-2-hydroxy 2-pyridin-3-yl-ethylamino)propyl]-1H-indol-7-yloxy}acetic acid.2 trifluoroacetate (24 mg, yield: 57%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)=[CH:33][CH:32]=3)=[N:28]2)=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB([C:52]2[CH:53]=[C:54]([CH:58]=[O:59])[CH:55]=[N:56][CH:57]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.O1CCOCC1>[CH3:43][N:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:27]3[N:26]=[CH:25][C:24]4=[CH:23][CH:22]=[C:21]([C:52]5[CH:53]=[C:54]([CH:58]=[O:59])[CH:55]=[N:56][CH:57]=5)[N:29]4[N:28]=3)=[CH:36][CH:35]=2)[CH2:42][CH2:41]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(C=O)c5)n4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.3 %

Procedure:
Into a 8-dram vial, Palladium Acetate (0.00772 g, 0.0344 mmol), Triphenylphosphine (0.0264 g, 0.100 mmol) and 1,4-Dioxane (1 mL) were added and stirred at room temperature for 10 minutes. (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.250 g, 0.646 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde (0.3009 g, 1.291 mmol), N,N-Dimethylformamide (1 mL) and 1.50 M of Sodium carbonate in Water (5 mL, 8 mmol) were added. The reaction mixture was heated at 90° C. overnight. The reaction was cooled to room temperature. Solvent was removed under vacuum to give a yellow solid. The resulting solid was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-pyridine-3-carbaldehyde as a yellow solid (65 mg, 24%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:18][C@@H:17](OS(C)(=O)=O)[CH2:16][C@H:11]2[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[C:1]1([S:7]([N:10]2[CH2:18][C@H:17]([N:24]=[N+:25]=[N-:26])[CH2:16][C@H:11]2[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1S(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1S(=O)(=O)c1ccccc1
Temperature: -60 °C
Yield: 84.2 %

Procedure:
In a 50 mL flask were combined 16 (0.60 g, 1.65 mmol) and 1.07 g (16.5 mmol, 10 equiv.) of sodium azide (Aldrich) in 10 mL of anhydrous DMF. The colorless solution was heated at −60° C. under a CaCl2 drying tube overnight, then allowed to cool and filtered. The flask and filter solids were washed with EtOAc, and the filtrate concentrated to dryness. The white residue was dissolved in EtOAc, washed twice with water, then brine, dried (MgSO4), filtered, and concentrated to give a pale yellow, waxy solid. This was recrystallized from EtOAc/hexanes to give 0.43 g (1.39 mmol, 85%) of 17 as fine white needles. 1H-NMR (400 MHz, CDCl3, δ ppm) 7.86 (dt, J=1 Hz, 8 Hz, 2H), 7.61 (tt, J=1 Hz, 8 Hz, 1H), 7.54 (tt, J=1Hz, 8 Hz, 2 H), 4.29 (t, J=8 Hz, 1H), 4.18 (m, 1H), 3.74 (s, 3H), 3.69 (q, J=5 Hz, 1H), 3.41 (dd, J=3 Hz, 11 Hz, 1H), 2.17 (m, 2H); 13C-NMR (400 MHz, CDCl3, 6 ppm) 179.46, 145.01, 140.85, 136.81, 135.14, 67.03, 66.97, 60.71, 60.37, 44.03; m/z: 311 (M+1)+. The trans-stereochemistry was confirmed by X-ray crystal structure.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([CH2:29][C:30]([OH:32])=[O:31])[C:23]=3[O:22][N:21]=2)=[CH:16][CH:15]=1.CI.Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][CH:29]([C:28]1[C:23]2[O:22][N:21]=[C:20]([C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)[C:24]=2[CH:25]=[CH:26][CH:27]=1)[C:30]([OH:32])=[O:31]
Reactant: O=C(O)Cc1cccc2c(-c3ccc(Cl)cc3)noc12
Reactant: [Li]CCCC
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cccc2c(-c3ccc(Cl)cc3)noc12
Temperature: 5 °C

Procedure:
n-Butyl lithium (31ml, 46m Mole of 1.5M) was cooled to -30°C under nitrogen with stirring and treated with a solution of diisopropylamine (6.25 ml. 4.65g., 46m Mole) in tetrahydrofuran (38ml) keeping the temperature at -30° to -50°C. A solution of the acetic acid of Example 35 (4.5g, 15.64m Mole) in THF (38ml) and hexamethylphosphoramide (38ml) was added dropwise to the Bu Li solution and the solution stirred at -30° to -40°C for 1.5 hours. It was then transferred to a solution of methyliodide (150ml) which was stirred and had been cooled to 5° C. in an ice bath. The mixture was stirred in the melting ice bath for 1.5 hours, acidified with a little conc. HCl, evaporated to small bulk and treated with water (500ml). The mixture was extracted with chloroform which was dried (Na2SO4) and evaporated to leave the α-methyl acetic acid as a mixture with its methyl ester. This was refluxed with conc. HCl (60ml) and acetic acid (30ml) for four hours, diluted with water, extracted with chloroform, which was dried (Na2SO4), evaporated to leave a gum which was purified on preparative thin layer chromotography to give the α-methyl acetic acid (0.85g), m.p. 136°-138°C.
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:10]=[CH:9][C:6](C=O)=[C:5]([C:11]#[CH:12])[CH:4]=1.[C:15](=[O:18])([O-])[O-].[Na+].[Na+]>CO>[C:11]([C:5]1[CH:6]=[CH:9][C:10]([CH:15]=[O:18])=[CH:3][CH:4]=1)#[CH:12]
Reactant: C#Cc1cc([Si](C)(C)C)ccc1C=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1ccc(C=O)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
The trimethylsilyl groups were subsequently subjected to a deprotecting reaction in accordance with reaction (2) in FIG. 2. Specifically, 4.0 g of 4-trimethylsilyl ethynyl benzaldehyde was dissolved in 20 mL of methanol, the solution was stirred for 30 minutes under nitrogen gas, 0.19 g of sodium carbonate was added, and the product was stirred for another 3 hours at room temperature. The solvent was removed at a reduced pressure, the residue was washed with a 5% aqueous solution of sodium bicarbonate and extracted with dichloromethane, anhydrous sodium sulfate was added, and the product was dried. The dried product was filtered off and the solvent was removed at a reduced pressure. The product was dried in a vacuum, yielding the target compound 4-ethynyl benzaldehyde with an aldehyde odor as white crystals with the yield of 99%.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)=O)C>C(Cl)Cl>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]=[O:13])=[N:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: O=Cc1ccc([N+](=O)[O-])cn1
Temperature: 5 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
Diisobutylaluminium hydride (1 M in DCM, 44 mL, 44 mmol, 1.3 equiv) was added dropwise to a cold (−78° C.) solution of 5-nitro-pyridine-2-carboxylic acid ethyl ester (step 39.4) (6.56 g, 33.5 mmol) in DCM (130 mL), under an argon atmosphere. The reaction mixture was allowed to warm to 5° C., quenched by addition of an aqueous solution of potassium sodium tartrate, diluted with DCM and H2O, stirred for 16 h at rt, and filtered through a pad of celite. The filtrate was extracted several times with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by by silica gel column chromatography (EtOAc/Hex, 1:1) to provide 2.54 g of the title compound as a beige solid: ESI-MS: 151.1 [M−H]−.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].ClC1C([CH2:21][CH:22]=[O:23])=CC=C(F)C=1C#N>>[F:10][C:7]1[C:4]([C:5]#[N:6])=[C:3]([CH3:11])[C:2]([CH2:21][CH:22]=[O:23])=[CH:9][CH:8]=1
Reactant: N#Cc1c(F)ccc(CC=O)c1Cl
Reactant: Cc1c(Br)ccc(F)c1C#N
Product: Cc1c(CC=O)ccc(F)c1C#N

Procedure:
6-Fluoro-2-methyl-3-(2-oxoethyl)benzonitrile was prepared in two steps starting from 3-bromo-6-fluoro-2-methylbenzonitrile in an analogous fashion to that described for the synthesis of 2-chloro-6-fluoro-3-(2-oxoethyl)benzonitrile (Steps B and C) above.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:2]1.Cl[CH2:17][CH:18]([C:20]1[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH:21]=1)[OH:19].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CN(C)C=O>[O:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[O:22][CH2:21][CH:20]1[CH:18]([OH:19])[CH2:17][N:13]1[CH2:12][CH:11]=[C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:15][CH2:14]1
Reactant: OC(CCl)C1=COc2ccccc2O1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CN1CC=C(c2c[nH]c3ccccc23)CC1)C1COc2ccccc2O1
Temperature: 100 °C
Yield: 26.3 %

Procedure:
A mixture of 5 g of the product of Step A, 5.4 g of α-(chloromethyl)-1,4-benzodioxin-2-methanol, 5.5 g of sodium carbonate, 4.2 g of potassium iodide and 100 ml of dimethylformamide was heated at 100° C under nitrogen for 24 hours and was then cooled and filtered. The filtrate was poured into ice and the gum formed was extracted with methylene chloride. The organic phase was washed, dried over calcium chloride and evaporated to dryness. The brown oily residue was chromatographed over silica gel and was eluted with a 98-2 methylene chloride-methanol mixture. The combined eluates were evaporated to dryness and the residue was crystallized from isopropanol to obtain 2.5 g of α-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-([1H]-indol-3-yl)-1,2,3,6-tetrahydro-1-pyridine-ethanol melting at 177° C.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:16]([OH:18])=[O:17])[CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(OCC)(=O)C>[Pd].C(O)(C)C.O>[C:9]1([C:12]2([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][CH2:15]2)[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C1(c2ccccc2)CCC1
Temperature: 65 °C
Reaction time: 4.5 h
Yield: 73.7 %

Procedure:
A stirred suspension of palladium on carbon (3.6 g, 5%) in isopropanol (200 mL) was treated in one portion with a solution of ammonium formate (9 g) in water (12.5 mL) followed by a solution of 1-(4-chloro-phenyl)-cyclobutanecarboxylic acid (15 g) in isopropanol (150 mL) also in one portion. The resultant suspension was stirred at 65° C. for 30 minutes and then treated with a further aliquot of a solution of ammonium formate (9 g) in water (12.5 mL). After stirring at 65° C. for a further 4.5 hours the reaction mixture was filtered through Hyflo and the filter pad was washed three times with isopropanol (75 mL). The combined filtrate and washings were evaporated. The solid obtained after standing at room temperature for 3 days was treated with ethyl acetate (350 mL) and water (150 mL) and the organic phase was separated, then dried over magnesium sulfate and then evaporated to give the title compound (9.25 g) as a white solid. LC-MS: RT=3.08 minutes, MS(ES+): very weak 177(M+H)+.