Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccccc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (65 mg, 0.189 mmol) and benzenesulfonyl chloride (0.029 mL, 0.227 mmol), the title compound was obtained as an off white solid (60 mg, 65% yield). MS (ESI): 484 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(OCC)(=O)C.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Br)cc1)N1CCOCC1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(CCc1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of Example 4A (4.405 mmol) in 1:1 ethyl acetate/ethanol (50 mL) was treated with Wilkinson's catalyst (815 mg, 0.880 mmol), degassed three times by freeze-thaw cycle, heated to reflux under nitrogen atmosphere for 2 days, and cooled to room temperature. The solution was adsorbed onto silica gel and purified by flash column chromatography with 50% ethyl acetate in hexane to provide the desired product (1.024 g, 78%). 1H NMR (300 MHz, CD3OD) δ 7.40 (2H, d), 7.10 (2H, d), 3.62 (4H, m), 3.57 (2H, t), 3.38 (2H, t), 2.94 (2H, t), 2.58 (2H, t).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:40])/[C:17](/[CH3:39])=[CH:18]/[CH:19]=[C:20](\[CH3:38])/[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1>O1CCOCC1>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])/[C:20](/[CH3:38])=[CH:19]/[CH:18]=[C:17](\[CH3:39])/[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:40])([OH:30])=[O:29]
Reactant: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 16 %

Procedure:
Using General Procedure B with 1.14 9 (2.09 mmol) (2 E,4 E)-(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid benzyl ester and with dioxane as solvent afforded 127 mg (16%) of the title compound as a white solid. MS mie (%): 365 (M+H+, 100).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]([F:19])([F:18])[C:12]([O:14][CH2:15][CH2:16]Cl)=[O:13].O>CS(C)=O>[O:7]([C:12]1([C:11]([F:19])([F:18])[F:10])[O:14][CH2:15][CH2:16][O:13]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(OCCCl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)C1(Oc2ccccc2)OCCO1
Yield: 47.1 %

Procedure:
A solution of 23.5 g (0.25 mol) of phenol in 50 mL of DMSO was added dropwise to a stirred suspension of 12.0 g (0.25 mol) of 50% NaH in mineral oil in 100 mL of DMSO maintained at 15°-20° by cooling. After evolution of gas had slowed, cooling and stirring were continued while 44.3 g (0.25 mol) of 2-chloroethyl trifluoroacetate were added. The temperature of the reaction mixture was kept below 30° while the exotherm which occurred subsided, then the resulting mixture was stirred overnight, poured into 1 L of water, and extracted with 200 mL, then two 100 mL portions, of ether. The resulting ether solutions were washed with water, dried over CaSO4, and distilled to give 27.6 g (47% yield) of 2-phenoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 52°-54° at 80 Pa (0.6 mm). IR (neat) and NMR (CCl4) spectra were consistent with the assigned structure.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([C:21]=3[NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)[C:19]#[N:20])[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(Cl)Cl.CN1C(=O)CCC1>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:21]3[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=3[C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([C:6]4[S:7][C:3]([CH2:1][N:50]5[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]5)=[CH:4][CH:5]=4)[CH:9]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cncc(-c2cccc(-c3ccc(C=O)s3)c2)c1Nc1ccc2[nH]ccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN1CCN(Cc2ccc(-c3cccc(-c4cncc(C#N)c4Nc4ccc5[nH]ccc5c4)c3)s2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To 5-[3-(5-formyl-2-thienyl)phenyl]-4-(1H-indol-5-ylamino)nicotinonitrile 150 (100 mg, 0.238 mmol) in CH2Cl2 (5 mL) and NMP (0.5 mL), cooled with ice-water bath, was added Na(OAc)3BH (264 mg, 1.2 mmol) and N-methylpiperazine (133 μL, 1.2 mmol). The resulting mixture was stirred at r.t. overnight and partitioned between CH2Cl2 and aq. NaHCO3. The combined organics were dried over Na2SO4, concentrated and purified by preparative TLC eluting with 10% MeOH/CH2Cl2 to give 63 mg (53% yield) of the title compound as a light yellow solid. MS: 505.2 (M+H); melting range: 120-123° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(O)(=O)C.[NH2:32][CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:37][N:36]([CH3:38])[C:34]([CH2:33][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13])=[O:35]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 80.2 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (38 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (39 mg), 2-amino-N,N-dimethyl-acetamide acetic acid salt (48 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 478. 1H NMR (DMSO-d6, 400 MHz): δ 12.49 (br, 1H), 8.46 (t, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.82 (m, 2H), 7.68 (m, 1H), 7.53 (d, 1H), 4.13 (d, 2H), 3.66 (s, 3H), 3.04 (s, 3H), and 2.87 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11](NC3C=C(C=CC=3F)C(O)=O)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[NH2:24][C:25]1[C:26]([CH3:35])=[N:27][CH:28]=[C:29]([CH:34]=1)[C:30]([O:32][CH3:33])=[O:31]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:24][C:25]3[C:26]([CH3:35])=[N:27][CH:28]=[C:29]([CH:34]=3)[C:30]([O:32][CH3:33])=[O:31])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: COC(=O)c1cnc(C)c(N)c1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Product: COC(=O)c1cnc(C)c(NC(=O)c2cnc3cc(Br)ccn23)c1

Procedure:
The title compound was prepared from 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1A, step 3) and methyl 5-amino-6-methylnicotinate (step 2) analogously to Intermediate 1A;
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][N:2]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1)[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CNc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: CN(CCN1CCCCC1)c1nc2ccc([N+](=O)[O-])cc2s1

Procedure:
The title compound is prepared according to the general procedure outlined in Example 61, Step 2, utilizing methyl(6-nitro-benzothiazol-2-yl)-amine (979 mg, 4.68 mmol) and N-(2-chloroethyl)-piperidine hydrochloride (2.01 g, 10.92 mmol) to yield 1.43 g (79%) of the product. mass spectrum (ion-spray): (m/z)=321.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:38]1([CH2:37][CH2:19][C:18]2[O:17][N:16]=[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:14]=2[C:11]2[O:10][C:9]([C:8]3[CH:7]=[CH:6][C:5]([NH2:26])=[CH:4][C:3]=3[O:2][CH3:1])=[N:13][N:12]=2)[CH2:40][CH2:39]1
Reactant: BrCC1CC1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2CCC2CC2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12.2 %

Procedure:
To a suspension of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF were added N,N-diisopropyl ethyl amine (128 μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) and the reaction mixture was stirred for 24 h at ambient temperature. After addition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL, 0.75 mmol) was added stirring was continued for 15 min and further bromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirring for 18 h at ambient temperature further bromomethyl-cyclopropane (0.12 mL, 1.2 mmol) was added and stirring continued for 24 h at this temperature. The reaction mixture was extracted with aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 0:80:20) afforded the title compound (28 mg, 12%) as a light brown solid. MS: m/e=403.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:9]1[C:8]2[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Temperature: 25 °C
Yield: 82.2 %

Procedure:
To a suspension of 8-nitro-4-(3-(trifluoromethyl)phenoxy)quinoline (200 mg, 0.60 mmol) and iron powder (267 mg, 4.77 mmol) in EtOH (3 mL) was added a solution of NH4Cl (312 mg, 5.89 mmol) in water (2 mL) and the reaction mixture was heated at reflux for 2 h. Then the reaction mixture was cooled to rt and filtered. The filtrate was concentrated and the concentrate was dissolved in CHCl3. The organic layer was washed with an aq. saturated solution of NaHCO3 and brine. The organic layer was separated, dried, filtered and concentrated to afford 150 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.58 (d, J=4.8 Hz, 1H), 7.77-7.65 (m, 3H), 7.55 (d, J=7.8 Hz, 1H), 7.32 (m, 2H), 6.64 (m, 1H), 6.71 (d, J=4.8 Hz, 1H), 6.00 (br s, 2H); MS (m/z): 305.22 (M+H)+.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:20]=1[C:21]([OH:23])=[O:22])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1>CO.O.[Pd]>[CH3:28][C:24]1[C:20]([C:21]([OH:23])=[O:22])=[C:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH2:11])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cccc(NC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1cccc(NC(=O)[C@@H](N)C(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.4 %

Procedure:
1.21 g of 2-[(N-benzyloxycarbonyl-L-valyl)amino]-6-methylbenzoic acid was dissolved in a mixture of 99 ml of methanol and 1 ml of water, followed by adding 200 mg of 10% Pd-C. The mixture was stirred for 3 hours at room temperature under a hydrogen atmosphere. Pd-C was filtered off and the filtrate was concentrated to give 830 mg of 6-methyl-2-(L-valylamino)benzoic acid.
Reaction SMILES: [Na].C([C@H:10]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:11][CH2:12][P:13]([O:18][CH2:19]C)(=[O:17])[O:14][CH2:15]C)(=O)C1C=CC=CC=1.CC(O)=[O:41]>CO>[CH2:23]([O:22][CH2:21][C@@H:10]([OH:41])[CH2:11][CH2:12][P:13]([O:18][CH3:19])(=[O:17])[O:14][CH3:15])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CCP(=O)(OCC)OCC)C(=O)c1ccccc1
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)CCP(=O)(OC)OC
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To 100 mL of dry MeOH was added 0.18 g (7.83 mmol) of sodium metal. After the sodium metal had completely disappeared, a solution of 3.91 g (7.05 mmol) of benzoyl phosphonate 5 in 10 mL of dry MeOH was added. After the mixture was stirred overnight, the reaction was quenched by addition of 500 μL (8.73 mmol) of AcOH and then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (elution with CHCl3/MeOH 10:1) to provide 2.56 g (86%) of hydroxy phosphonate 6 as a colorless oil; [α]25D −5.20° (c 5.0, C6H6); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=6.8 Hz), 1.26 (br s, 26H), 1.54-1.58 (m, 2H), 1.70-1.90 (m, 4H), 2.78 (br s, 1H), 3.29 (dd, 1H, J=7.1, 9.4 Hz), 3.40-3.48 (m, 3H), 3.74 (d, 6H, J=10.8 Hz), 3.70-3.85 (m, 1H); 13C NMR (CDCl3) δ 14.0, 20.7 (d, J=142.1 Hz), 22.6, 26.0, 26.1 (d, J=4.7 Hz), 29.3, 29.4, 29.5, 29.6, 31.9, 52.3, 69.8 (d, J=14.8 Hz), 71.6, 74.4; MS (electrospray) MH+ m/z calcd for C22H48O5P 423.3, found 423.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:7]=1[C:8]#[N:9].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:3]1[C:2]([Cl:1])=[C:7]([C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:5][N:4]=1)[C:8]#[N:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(-c2c[n+]([O-])cc(Cl)c2C#N)c1
Product: COc1cccc(-c2cnc(Cl)c(Cl)c2C#N)c1
Reaction time: 1 h

Procedure:
A mixture of crude 3-chloro-4-cyano-5-(3-methoxyphenyl)pyridine 1-oxide from Step 2 and phosphorus oxychloride (15 mL) in a sealed tube was placed in a 100° C. bath. After 1 h at 100° C., HPLC analysis indicated that a 2:1 mixture of products was formed. The mixture was concentrated. Recrystallization from ethyl acetate/hexanes (10 mL/10 mL) gave 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile as white solid (200 mg). The mother liquor was purified by reverse phase HPLC, using Sunfire S10 30×250 mm column and eluting with 80-100% solvent B (90% methanol-10% water-0.1% TFA) in solvent A (10% methanol-90% water-0.1% TFA), to give additional 2,3-dichloro-5-(3-methoxyphenyl)isonicotinonitrile (400 mg). 1H NMR (500 MHz, methanol-d4) δ ppm 8.54 (1H, s), 7.45 (1H, t, J=7.97 Hz), 6.77-7.28 (3H, m), 3.86 (3H, s); MS (ES+) m/z: 279 (M+H); LC retention time: 3.768 min (analytical HPLC Method A). No attempt was made to isolate the undesired 2,5-dichloro-3-(3-methoxyphenyl)isonicotinonitrile isomer.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][N:20]=2)[N:15]=1.Cl[C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:26].O>CN(C)C=O>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:25]([O:13][CH:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4](=[O:3])[N:5]2[C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[O:26])[CH2:28][CH2:29]1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ncccc2n1
Reactant: CN1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ncccc3n2)CC1
Temperature: 13 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
A suspension of sodium hydride (50% dispersion in mineral oil) (1.46 g.) in anhydrous dimethylformamide (80 cc.) is added to a suspension of 3-hydroxy-2-(1,5-naphthyridin-2-yl)isoindolin-1-one (7 g.) in anhydrous dimethylformamide (410 cc.). When the evolution of gas has ceased, a solution of 1-chlorocarbonyl-4-methyl-piperazine (4.6 g.) in anhydrous dimethylformamide (25 cc.) is added dropwise. After stirring for 4 hours, the reaction mixture is poured into water (3,000 cc.) cooled to 13° C. The precipitate is filtered off, washed with water (75 cc.) and then dried to yield 3-(4-methylpiperazin-1-yl)carbonyloxy-2-(1,5-naphthyridin-2-yl) isoindolin-1-one (5.7 g.) melting at 170°-171° C. After recrystallisation from acetonitrile (50 cc.), the products melts at 173° C.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([C:25]([NH2:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24]>>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C:25]([NH2:30])([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(N)(CC)CC
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Product: CCC(N)(C#Cc1ccc(N2C[C@@H](O)[C@H](OC)C2)nc1Cc1ccccc1)CC

Procedure:
This was synthesized in the same manner as in Example 6 except that 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1) and 1,1-diethyl-2-propynylamine were used.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][Cl:27]>>[Cl:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: ClCCCBr
Reactant: O=C1NCCCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1NCCCn2c1cc1cc(OCCCCl)ccc12
Yield: 35 %

Procedure:
The title compound was synthesized in analogy to example 2, intermediate, from 9-hydroxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (example 15, intermediate a)), potassium carbonate and 1-bromo-3-chloropropane, to give the desired compound as a light yellow solid (35%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(NC(C)C)(C)C.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.[Cu](I)I>[CH3:12][Si:13]([CH3:15])([CH3:14])[C:16]#[C:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cccc2ccccc12
Temperature: 80 °C
Yield: 88.8 %

Procedure:
Under an argon atmosphere, 50 g (0.241 mol) of 1-bromonaphthalene, 2.5 g (3.6 mmol) of bis(triphenylphosphine)palladium(II) dichloride and 0.68 g (3.6 mmol) of copper Iodide were dissolved in 500 ml of diisopropylamine in a 1 L 3-necked flask equipped with a stirrer, thermometer and reflux condenser. 35.6 g (0.362 mol) of trimethylsilyl acetylene was slowly dropped into the resulting mixture at room temperature. The reaction mixture was slowly heated to 80° C. and refluxed 12 hours. After the reaction was completed, the reaction mixture was cooled down to room temperature. The precipitated salt was filtered off, and the solvent was removed from the filtrate under a reduced pressure. The residue was dissolved in methylene chloride. The organic layer was washed with water several times and then dried with anhydrous magnesium sulfate. The solvent was removed, to obtain a liquid. The obtained liquid was purified by silica gel column chromatography using hexane as an eluent, to give a colorless viscous liquid. The liquid was recrystallized from ethanol to give white crystal in needle-shape. The white crystal was recovered and then sufficiently dried at room temperature, to give 48 g (88.9% yield) of the desired product having a melting point of 41-43° C.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=[CH2:4].[CH3:7][C:8]([CH3:10])=O.COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:10])[O:5][CH:2]([CH:3]=[CH2:4])[CH2:1][O:6]1
Reactant: C=CC(O)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: c1ccccc1
Product: C=CC1COC(C)(C)O1
Reaction time: 3 h
Yield: 56.7 %

Procedure:
3-Butene-1,2-diol (5.00 g, 56.7 mmol), acetone (9.88 g, 170 mmol), 2,2-dimethoxy propane (17.7 g, 170 mmol), and p-toluene sulfonic acid (1.62 g, 8.5 mmol) were added to benzene (100 mL). After 16 hours of reflux, starting material was observed by TLC. 2,2-Dimethoxy propane (9.99 g, 95.1 mmol) and acetone (1.58 g, 27.3 mmol) were then added, followed by an additional 3 hour reflux. The mixture was washed with saturated aqueous NaHCO3 and extracted with EtOAc (3×40 mL). The organic extracts were dried over MgSO4, filtered, concentrated and purified by column chromatography (5% ethyl acetate in hexanes) to provide the titled compound (4.12 g, 57%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[H-].[Na+].[Cl:14][C:15]1[C:24](Cl)=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>O1CCOCC1>[Cl:14][C:15]1[C:24]([O:7][CH2:6][CH2:5][O:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: OCCOc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccccc1OCCOc1nc2ccccc2nc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(2-Chlorophenoxy)ethanol (0.229 g, 1.33 mmol) was treated with NaH (55% dispersion in mineral oil; 0.058 g, 1.33 mmol) in dioxane (2 mL). After stirring at room temperature for 3 h, the mixture was added dropwise to a slurry of 2.3-dichloroquinoxaline (0.320 g, 1.60 mmol) in dioxane (1 mL). The resulting mixture was stirred at room temperature for 15 h to produce the intermediate 2-chloro-3-[2-(2-chlorophenoxy)ethoxy]quinoxaline which was used directly in the next step.