Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([OH:34])[C:32]#[CH:33])=[CH:27][CH:26]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([OH:34])[C:32]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:33]=2)=[CH:29][CH:30]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC(O)c1ccc(Br)cc1
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1C(O)c1ccc(Br)cc1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-(4-bromophenyl)prop-2-yn-1-ol. MS (+ESI) m/z: 483.0.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=3)=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O1CCOCC1.[ClH:56]>O>[ClH:56].[CH3:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2ccccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2ccccc2n1
Reaction time: 72 h

Procedure:
A mixture of 2-methyl-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline (A) (890 mg) and a 7.5M solution of hydrogen chloride dioxane (10 ml) and water (1 ml) was allowed to stand for 72 hours. Volatile material was removed by evaporation and the residue was triturated with ether (2×50 ml). The ether was decanted off and the solid residue crystallised from isopropanol to give 2-methyl-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]quinoline hydrochloride (370 mg), as a white solid, m.p. 188°-190° C.; NMR (d6 -DMSO): 2.92(s,3H), 5.63(s,2H), 7.21(d,2H), 7.56-7.87(m,8H), 8.07(dt,1H), 8.28(dd,1H), 8.32(dd,1H); mass spectrum [-ve FAB, DMSO/NBA]: 392 (M-H)-, 158; microanalysis found: C,66.0; H,4.6; N,15.5%; C24H19N5O.HCl.0.5H2O requires: C,65.7; H,4.8; N,16.0%.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7]=1[Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[Cl:15][C:12]1[CH:13]=[C:14]2[C:6]([CH2:5][CH2:4][NH2:1])=[C:7]([Si:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:21][CH3:22])[NH:8][C:9]2=[N:10][CH:11]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Yield: 62 %

Procedure:
A mixture of 3-(2-azidoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.900 g; 2.68 mmol) and triphenylphosphine 1.05 g; 4.02 mmol) in methanol (25 mL) was stirred at 80° C. for 1 hour and was concentrated under reduced pressure. The residue was dissolved in toluene (15 mL). Hydrochloric acid (2 mL) and water 15 mL were added. After separation of the two layers, the aqueous solution was extracted with 3×15 mL of toluene and was made alkaline by addition of a solution of sodium hydroxide 2N. The formed precipitate for filtered off. The filtrate was extracted with dichloromethane (5×15 mL). Combined dichloromethane extracts were dried over magnesium sulphate and was concentrated under reduced pressure to give 0.515 g (62%) of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine as an oily residue.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>O1CCCC1.CO>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:7]([OH:8])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC(c1ccccc1)c1ccc(Cl)cc1
Yield: 93.4 %

Procedure:
15.2 g (0.07 mole) of phenyl-(4-chlorophenyl)-ketone are dissolved in 30 ml of tetrahydrofuran and 10 ml of methanol. 1.32 g (0.035 mole) of sodium borohydride are gradually added, with stirring, and the exothermic reaction is maintained between 25° and 30° C. by cooling. After one hour ketone can no longer be detected by thin layer chromatography. The mixture is then extracted with water and chloroform, the chloroform is dried with sodium sulfate and removed in a rotary evaporator. The crude yield is 16.2 g (oil). Of this 15.5 g are distilled at 220° C. and 30 mbar in a bulb tube oven. 14.3 g of an oil are obtained which is more than 95% pure according to gas chromatography and solidifies into crystals on cooling. 13.3 g are recrystallised from a mixture of 25 ml of n-hexane and 5 ml of cyclohexane. The yield is 12.2 g; m.p. 58°-60° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH3:4][C:5]([CH3:11])([C:9]#[CH:10])[C:6]([OH:8])=[O:7]>CCOCC>[CH3:4][C:5]([CH3:11])([C:9]#[CH:10])[C:6]([O:8][CH3:3])=[O:7]
Reactant: C#CC(C)(C)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: C#CC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a solution of diazomethane (10 g) in ether (400 mL) was added dropwise 2,2-dimethyl-but-3-ynoic acid (10.5 g, 93.7 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. The mixture was distilled under atmospheric pressure to give crude methyl 2,2-dimethylbut-3-ynoate (14 g), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 2.28 (s, 1H), 1.50 (s, 6H).
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=2)[CH:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[CH3:37])[CH3:2].[ClH:38].[CH3:39][C:40]1[C:45]([C:46]([OH:48])=O)=[C:44]([CH3:49])[N:43]=[CH:42][N:41]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[ClH:38].[ClH:38].[CH2:1]([O:3][C@@H:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:10]=2)[C@H:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:28][CH2:27][N:26]([C:46]([C:45]3[C:40]([CH3:39])=[N:41][CH:42]=[N:43][C:44]=3[CH3:49])=[O:48])[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[CH3:37])[CH3:2]
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: CCOC1Cc2cc(C(F)(F)F)ccc2C1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCO[C@@H]1Cc2cc(C(F)(F)F)ccc2[C@H]1N1CCN(C2(C)CCN(C(=O)c3c(C)ncnc3C)CC2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
t-Butyl 4-{(3S)-4-[2-ethoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (48.4 g, 0.0921 mol) was treated with a 4.0 M solution of hydrogen chloride in 1,4-dioxane (230 mL) at room temperature for 1 h. The reaction mixture was concentrated to dryness and the residue was further dried under high vacuum. The formed amine hydrochloride was mixed with 4,6-dimethyl-pyrimidine-5-carboxylic acid (16.80 g, 0.110 mol) in methylene chloride (100 mL), and then 1-hydroxybenzotriazole (16.80 g, 0.1243 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (25.00 g, 0.1304 mol) and triethylamine (65.0 mL, 0.466 mol) were added. The resulting reaction mixture was stirred at room temperature overnight before it was diluted with methylene chloride and washed with aqueous sodium hydroxide (1 M) and brine. The organic layer was collected and dried over magnesium sulfate. After removal of the solvent, the residue was dissolved in methylene chloride (50 mL) and the solution was passed through a silica plug with ethyl acetate containing 1% triethylamine. The solution was concentrated and the residue was dissolved in 900mL of isopropyl acetate. To the above solution, 185 mL of 1.0 N HCl in isopropyl acetate was slowly added. The mixture slowly turned cloudy, and was stirred overnight. The formed white solid was collected, washed with 40 mL of isopropyl acetate. The cake was air-dried to give 47.0 g (80.7%) of product. MS (EI) 560.3 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])[C:3]#[N:4].[NH:13]=[C:14](SC)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCOCC1>[NH2:4][C:3]1[NH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:1][C:2]=1[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: CCOC(=O)C(=N)SC
Reactant: N#CC(N)Cc1ccccc1F
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(Cc2ccccc2F)c(N)[nH]1

Procedure:
A solution of 0.90 g (5.45 mmol) of 2-amino-3-(2-fluorophenyl)propanenitrile from example 8A and 2.20 g (9.27 mmol) of ethyl imino(methylthio)acetate [D. Catarzi et al., J. Med. Chem. 1995, 38, 2196-2201] in 10 ml of dioxane is stirred at RT for two days. The solution is then concentrated in vacuo, and the residue is purified by preparative HPLC. 770 mg (54% of theory) of the desired product are obtained.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([I:8])[N:3]=1.[Na].[CH2:10]([OH:12])[CH3:11]>>[I:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:12][CH2:10][CH3:11])[N:3]=1
Reactant: CCO
Reactant: Ic1cncc(I)n1
Agent: [Na]
Product: CCOc1cncc(I)n1

Procedure:
2,6-Diiodopyrazine (12 g, 36.14 mmol) was added to a solution of sodium (0.83 g, 36.10 mmol) in ethanol (75 ml). The solution was refluxed for 1 h, the solvent removed under vacuum, water (40 ml) added and extracted into dichloromethane (4×200 ml). The solvent was removed under vacuum and the residue chromatographed through silica-gel using dichloromethane as eluant to give 2-iodo-6-ethoxy pyrazine (6.5 g). m.p. 36°-37° C.; δ (60 MHz, CDCl3) 1.30 (3H, t, J=7 Hz, Me); 4.35 (2H, q, J=7 Hz, CH2Me); 8.07 (1H, s, pyrazine-H): 8.35 (1H, s, pyrazine-H).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])[CH:42]=[CH:41][C:40]=1[Cl:51]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:41]1[CH:42]=[C:43]([S:45]([CH:48]([CH3:49])[CH3:50])(=[O:46])=[O:47])[CH:44]=[CH:39][C:40]=1[Cl:51])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)S(=O)(=O)c1ccc(Cl)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-bromo-1-chloro-4-(isopropylsulfonyl)benzene (Intermediate 129), the title compound was obtained as a white solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[P:12]([O-:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].[F-].[K+]>C(Cl)Cl>[OH:8][CH:7]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOP([O-])OCC
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(O)c1cccc([N+](=O)[O-])c1
Yield: 98.8 %

Procedure:
m-Nitrobenzaldehyde (4.53 g, 30 mmol) was dissolved in diethyl phosphite (4.14 g, 30 mmol) under gentle heating. The solution was brought to room temperature and KF (8.7 g, 0.15 mole) was added with rapid stirring. After 30 min the mixture was suspended in CH2Cl2 (150 ml). The resultant suspension was filtered and the filtrate was concentrated under reduced pressure furnishing 8.57 g (99%) of 17 as a yellow colored solid, mp 93-95° C., IR (neat): 3750-3040, 1540, 1355, 1205 and 1050; 1H NMR (200 MHz, CDCl3): δ1.23 (6H, m), 4.10 (4H, m), 5.14 (1H, d, J=12 Hz), 5.94 (1H, s, OH) and 7.93 (4H, m); 13C NMR (50 MHz, CDCl3): δ17.6, 64.2, 64.9, 72.1, 122.4, 123.1, 129.3, 133.4, 139.8 and 148.3; HR-MS (EI): m/e 289.0715 (M+C11H16NO6P requires 289.0714).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH2:14])=[O:13])[CH:8]=[CH:7]2.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:15]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]3[C:11]=2[N:10]=[C:9]([C:12]([NH2:14])=[O:13])[CH:8]=[CH:7]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: NC(=O)c1ccc2cncc(Br)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: NC(=O)c1ccc2cncc(N3CCCCC3)c2n1
Temperature: 110 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
8-Bromo-1,6-naphthyridine-2-carboxamide (22.4 g, 99 mmol) produced in Example 12 (12a) was dissolved in piperidine (152 g, 1.78 mol), to which potassium carbonate (36.9 g, 267 mmol) and tetrabutylammonium iodide (TBAI) (11.8 g, 99 mmol) were then added, followed by stirring at 110° C. for four hours. Piperidine was distilled off under reduced pressure. Toluene and water were added to the residue thus obtained, and the resulting mixture was partitioned (the pH of the aqueous layer was adjusted to be weakly basic). The aqueous layer was extracted with dichloromethane again, and then combined with the toluene layer. The resulting mixture was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was sequentially purified by normal phase silica gel column chromatography ((after letting hexane:ethyl acetate, 50:50, flow through, applying ethyl acetate:methanol, 100:0-90:10, V/V), basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V), and reverse phase silica gel column chromatography (water:acetonitrile, 90:10-60:40, V/V) to give the desired title compound (15.7 g, yield 69%).
Reaction SMILES: [CH2:1]([C:6]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]([CH:9]([C:14]([O:16]C)=O)[C:10]([O:12][CH3:13])=[O:11])=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4].C1(C(CCC)(CCC)C(C(C(OCC)=O)C(OCC)=O)=O)C=CC=CC=1>>[OH:16][C:14]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:6]([CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[C:7](=[O:8])[C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C(=O)OC)C(=O)C(CCC(C)C)(CCC(C)C)c1ccccc1
Agent: CCCC(CCC)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Product: COC(=O)C1=C(O)c2ccccc2C(CCC(C)C)(CCC(C)C)C1=O

Procedure:
The title compound was prepared according to the procedure of Example 1F, substituting the product of Example 6E for the product of Example 1E. 1H NMR (300 MHz, CDCl3): δ 15.02 (d, J=4.04 Hz, 1 H), 8.21 (m, 1 H), 7.61 (m, 1 H), 7.41 (m, 2 H), 3.99 (s, 3 H), 2.26 (m, 2 H), 1.92 (m, 2 H), 1.30 (m, 2 H), 0.79 (m, 14 H), 0.47 (m, 2 H).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[Br:21])[OH:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCOC(C)=O.C(O[C:32]([CH3:35])([CH3:34])[CH3:33])(=O)C>>[C:1]([O:7][CH2:8][C@H:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:12]=1[Br:21])[O:10][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])cc(Br)c1[C@H](O)COC(=O)C(C)(C)C
Reactant: CC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
To a solution of (S)-2-(2-bromo-6-methyl-4-nitrophenyl)-2-hydroxyethyl pivalate (65E) in t-butyl acetate at 0° C., was added HClO4 (perchloric acid) (5.45 ml) slowly, stirred at 0° C. for 5 min, then the reaction mixture was warmed up to rt and stirred for 3 hs. The mixture was diluted by EtOAc, washed by sat. NaHCO3, extracted by EtOAc, dry over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-100% EtOAc in Hexanes to give 65F (9 g, 85%).
Reaction SMILES: [Br:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].CN(C)C(=O)C.CO.[BH4-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([Cl:10])[CH:7]=[CH:8][N:9]=1
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: OCc1c(Cl)ccnc1Br
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
To a solution of 2-bromo-4-chloronicotinaldehyde 160a (20 g, 90.4 mmol), N,N-dimethylacetamide (15.6 g, 180.8 mmol) and methanol (8.8 g, 271 mmol) in 1,4-dioxane (150 mL) was added sodium borohydride (1.7 g, 45.2 mmol). See FIG. 5. The mixture was stirred at 20° C. for 10 min. TLC (petroleum ether:ethyl acetate=1:1) showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous ammonium chloride solution (30 mL) and water (40 mL), and extracted with EtOAc (100 mL×2). The organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate from 50:1 to 1:1) to afford (2-bromo-4-chloropyridin-3-yl)methanol 160b (20 g, 95%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:11]([CH3:12])=[CH:10][C:8]([NH2:9])=[C:7]([CH3:13])[C:6]=1[Cl:14].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1.CCCCCC>[Cl:14][C:6]1[C:7]([CH3:13])=[C:8]([NH:9][C:26]([NH:25][C:23](=[O:24])[C:22]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:21]=2[F:20])=[O:27])[CH:10]=[C:11]([CH3:12])[C:5]=1[O:4][C:3]1[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:2]=1[CH3:1]
Reactant: Cc1ccc(Oc2c(C)cc(N)c(C)c2Cl)c(C)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(Oc2c(C)cc(NC(=O)NC(=O)c3c(F)cccc3F)c(C)c2Cl)c(C)c1
Temperature: 50 °C

Procedure:
Into a solution of 4-(2,4-dimethylphenoxy)-2,5-dimethyl-3-chloroaniline (1.75 grams, 6.3 mmol) prepared in Part B in 7 milliliters of toluene, which solution was warmed to a temperature of 50° C., was added 1.14 grams (6.2 mmol) of 2,6-difluorobenzoyl isocyanate in 1.5 milliliters of toluene. The reaction mixture was heated to a temperature of 90° C. and maintained at this temperature for 0.5 hours. After cooling to room temperature, the reaction mixture was diluted with 20 milliliters of hexane and then cooled in an ice bath. A precipitate formed which was collected by filtration and washed with a cold solution of 50% hexane in toluene. After vacuum drying, a white solid (1.26 grams) which was identified as 1-[3-chloro-4-(2,4-dimethylphenoxy)-2,5-dimethylphenyl]-3-(2,6-difluorobenzoyl)urea was obtained having a melting point of 183° C.-185° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH2:4][CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:1]=[C:2]1[CH:7]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: O=C(O)CCC/C=C\CC1C=CCCC1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C(O)CCC/C=C\CC1C=CCCC1=O
Reaction time: 0.17 h

Procedure:
A solution of 15.8 g of 7-(6-hydroxycyclohex-2-enyl)hept-5Z-enoic acid (as obtained by ether-pentane extraction as described above) in 300 ml of acetone was stirred with ice-bath cooling as 30 ml of standard Jones reagent was added dropwise. The resultant mixture was stirred for 10 min at 0° and then quenched by the addition of several ml of isopropyl alcohol. After stirring for another 10 min at 0° the solvents were removed by evaporation in vacuo. The residue was dissolved in water and extracted several times with ether. The combined ether extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to yield 13.0 g of crude 7-(6-oxocyclohex-2-enyl)hept-5Ztenoic acid as a yellow oil.
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[C:11]([F:12])=[CH:10][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:8][C:7]=2[F:23])[OH:5])[CH2:3][CH2:2]1.O([N+]1([O-])CCOCC1)C>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:1]1([C:4]([C:6]2[C:7]([F:23])=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)=[CH:10][C:11]=2[F:12])=[O:5])[CH2:3][CH2:2]1
Reactant: COc1ccc(COc2cc(F)c(C(O)C3CC3)c(F)c2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: CO[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(COc2cc(F)c(C(=O)C3CC3)c(F)c2)cc1
Reaction time: 0.33 h
Yield: 83.8 %

Procedure:
To a solution of cyclopropyl{2,6-difluoro-4-[(4-methoxybenzyl)oxy]phenyl}methanol (860 mg, 2.73 mmol) in DCM (137 mL) cooled to 0° C. via ice water bath was added 4-methoxylmorpholine N-oxide (481 mg, 4.10 mmol) followed by TPAP (96 mg, 0.27 mmol) and the resulting mixture was stirred for 20 minutes. The mixture was directly loaded onto a silica gel column (80 g, ISCO, eluting with a gradient of 10-30% ethyl acetate hexane) and purified to afford the title compound (728 mg, 85%). LC/MS 319 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[C:18](=[O:31])[CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O>FC(F)(F)C(O)=O>[CH3:1][N:2]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]([CH2:32][C:33]([OH:35])=[O:34])[C:18](=[O:31])[CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C(=O)c1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN1C(=O)c2ccccc2C1=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C(=O)c1ccccc1N(CC(=O)O)C(=O)CN1C(=O)c2ccccc2C1=O)c1ccccc1
Yield: 96.3 %

Procedure:
2-{N-[2-(N-Methylanilino)carbonylphenyl]-2-phthalimidoacetamideo}acetic acid may be prepared in the following manner: a solution of tert-butyl 2-{N-[2-(N-methylanilino)carbonylphenyl]-2-phthalimidoacetamido]acetate (7.9 g) in trifluoroacetic acid (30 cc) is stirred at a temperature in the region of 20° C. for 24 hours and then poured into water (50 cc). The aqueous phase is extracted with dichloromethane (3×250 cc). The organic phases are combined, washed with water (2×150 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. The residue is treated with petroleum ether (100 cc) and the insoluble product is separated by filtration and dried under reduced pressure (15 kPa) at 30° C. 2-{N-[2-(N-Methylanilino)carbonylphenyl]-2-phthalimidoacetamido}acetic acid (6.8 g) is thereby obtained in the form of an amorphous solid, which is used without further treatment in the subsequent syntheses.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][N:11]([CH:24]3[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22][CH2:23]3)[CH2:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Yield: 60 %

Procedure:
In operating analogously to preparation XXVIII, starting with N-benzylpiperazine and N-Boc-4-piperidinone, the product sought after is obtained as a colourless oil (yield=60%).