Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[F:19]>CS(C)=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH2:10])[CH:5]=2)=[CH:14][C:13]=1[F:19]
Reactant: Nc1ccc(O)cc1F
Reactant: Nc1cc(Cl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Yield: 26.3 %

Procedure:
Sodium hydride (1.1 g) was suspended in dimethyl sulfoxide (60 ml) under a nitrogen stream, and 4-chloro-2-pyridinamine (2.9 g) described in WO 02/32872 and then 4-amino-3-fluorophenol (3.6 g, 28 mmol) were added thereto at room temperature while stirring, followed by stirring under a nitrogen stream at 150° C. for 9 hrs. The reaction mixture was cooled down to room temperature, and partitioned between 10% aqueous ammonia (150 ml) and ethyl acetate (350 ml). The organic layer was washed twice with 10% aqueous ammonia (150 ml). The combined aqueous layer was extracted with ethyl acetate (150 ml) again. The combined organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate (100 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1, ethyl acetate, then ethyl acetate:methanol=10:1). Crude fractions containing the target compound were concentrated to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound (1.3 g, 26%) as a purple solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].BrN1C(=[O:16])CCC1=O>C(OCC)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[O:16]
Reactant: Cc1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)cc1Br
Temperature: 80 °C
Yield: 39.9 %

Procedure:
2-Bromo-4-fluorotoluene (10.215 g) was dissolved in ethyl acetate (100 ml), N-bromosuccinimide (11.3 g) and 70% benzoyl peroxide (200 mg) were added thereto, and the resulting mixture was stirred under heating at 80° C. for 1 hr. After the reaction solution was cooled, the resulting insoluble matters were filtered off. The resulting filtrate was washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and evaporated. The resulting residue was dissolved in acetic acid (30 ml), water (30 ml) and hexamethylene tetramine (15.141 g) were added thereto, and the resulting mixture was heated under stirring at 100° C. for 1 hr. To the mixture was added 38% hydrochloric acid (20 ml), which was then stirred for 1 hr, and then it was cooled as it was, and extracted with ethyl acetate. The resulting organic phase was washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless solid (4.376 g, yield; 41%).
Reaction SMILES: C(O[CH:4](OCC)[C:5]#[C:6][C:7]1[C:8](=[O:27])[N:9]([CH2:25][CH3:26])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])C.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][NH2:40])=[CH:35][CH:34]=1)#[N:32].S(=O)(=O)(O)O.O>C(#N)C>[CH2:25]([N:9]1[C:8](=[O:27])[C:7]([C:6]#[C:5]/[CH:4]=[N:40]\[NH:39][C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)=[C:12]([CH3:13])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[C:10]1=[O:24])[CH3:26]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CCOC(C#Cc1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(CC)c1=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC#N
Solvent: O
Product: CCn1c(=O)c(C#C/C=N\Nc2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of 5-(3,3-diethoxyprop-1-ynyl)-3-ethyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (2.40 g) in acetonitrile (72 ml) were added 4-cyanophenylhydrazine (1.11 g) and concentrated sulfuric acid (0.30 ml) and the resulting mixture was stirred at room temperature for thirty minutes. The resulting mixture was cooled to 0° C. and thereto was added water (140 ml) dropwise, and the solids were collected by filtration and washed with water to afford (Z)-4-(2-(3-(3-ethyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)prop-2-yneylidene)hydrazinyl)benzonitrile (2.50 g) as brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:22])=[CH:16]/[C:17](OCC)=[O:18])=[CH:11][CH:10]=1.CC(C[AlH]CC(C)C)C>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:22])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(Cl)c2Cl)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2cccc(Cl)c2Cl)cc1

Procedure:
(E)-Ethyl 3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-enoate (1.07 g, 3.19 mmol) was reduced with DIBAL-H by a procedure analogous to that described in example 52 b to give (E)-3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-en-1-ol as a colourless solid; 0.74 g (79%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C@@H:6]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:7][C:8]1[CH:32]=[CH:31][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH:18]([N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:23])[C:19]([OH:21])=O)=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:42]([S:61][CH2:62][C@@H:63]([C:65]([NH2:67])=[O:66])[NH2:64])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:41])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][CH:18]([N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[CH3:23])[C:19]([NH:64][C@@H:63]([CH2:62][S:61][C:42]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:65]([NH2:67])=[O:66])=[O:21])=[CH:31][CH:32]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCCC(C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)N(C)C(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
2.24 g (3.86 mmol) of the compound from example 7A was dissolved in 100 ml dichloromethane. 1.401 g (3.86 mmol) S-Trityl-L-cysteinamide, 0.67 ml (3.86 mmol) N,N-diisopropylethylamine and 1.47 g (3.86 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 3.26 g (2.75 mmol, 71% of theory, 78% purity) of the desired product as a mixture of diastereomers.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[NH:53]1[C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=[N:54]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:57]2[NH:53][N:54]=[CH:55][CH:56]=2)=[O:59])[CH2:25]1
Reactant: O=C(O)c1ccn[nH]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2ccn[nH]2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1H-pyrazole-5-carboxylic acid as the starting materials in 66% yield. LCMS for C26H25ClN9O2 (M+H)+: m/z=530.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5](=[O:20])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[CH:7]=[CH:8][CH:9]=1.N1C=CN=C1.[C:26]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O.O>[Si:30]([O:1][CH2:2][CH2:3][C:4]1[C:5](=[O:20])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[CH:7]=[CH:8][CH:9]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O
Reaction time: 8 h

Procedure:
38 g (138 mmol) of the compound from Example 14A are dissolved in 200 ml of anhydrous N,N-dimethylformamide, and 12.2 g (198 mmol) of imidazole and, a little at a time, 46 g (135 mmol) of tert-butyl(chloro)diphenylsilane are added at 0° C. The mixture is stirred overnight and then diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed twice with saturated sodium chloride solution, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is applied to silica gel and chromatographed using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and evaporated to dryness under reduced pressure. This gives 62 g (88% of theory) of the desired product.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:34]([C:35]([F:36])([F:38])[F:37])[C:27]=3[Cl:26])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Product: FC(F)(F)c1cccc(CNc2cccc(-c3c(Cc4ccccc4)nnc4c(Cl)cccc34)c2)c1Cl

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and 2-chloro-3-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 538.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10](O)=[O:11].CO.Cl>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[CH2:10][OH:11]
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@@H]1Cc2ccccc2N1
Reaction time: 2 h
Yield: 87 %

Procedure:
BH3-DMS solution (18.4 mmol, 2 eq) was added dropwise to a solution of (S)-indoline-2-carboxylic acid (9.2 mmol, 1.0 eq) in THF (18 ml) and the mixture was refluxed for 12 h. Methanol (7.5 ml) and concentrated HCl (2.5 ml) were added to the reaction mixture with cooling, then refluxing was continued for a further 2 hours. The solvent was removed under vacuum and the residue made alkaline with 40% NaOH solution and extracted with DCM. The organic phase was washed with saturated sodium chloride solution, dried (Na2SO4) and concentrated to small volume under vacuum. The crude product was processed by column chromatography. Yield: 87%
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:10]([O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:45]([O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[O:46]>>[CH2:37]([O:36][C:34]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH2:25][O:24][CH:10]2[CH:11]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:12]([CH2:14][CH2:15][CH3:16])[CH2:13][N:8]([C:45]([O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[O:46])[CH2:9]2)[CH:35]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C[Si](C)(C)CCOC(=O)Cl
Reactant: CCCC1CN(Cc2ccccc2)CC(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1c1ccc(F)cc1
Product: CCCC1CN(C(=O)OCC[Si](C)(C)C)CC(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 1(d), by reacting (3RS,4RS,5SR)-1-benzyl-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(4-fluoro-phenyl)-5-propyl-piperidine with β-trimethylsilylethyl chloroformate [Synthesis 346 (1987)] there was obtained 2-trimethylsilanylethyl (3RS,4RS,5SR)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(4-fluoro-phenyl)-5-propyl-piperidine-1-carboxylate as a pale yellow syrup, MS: 628 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[CH2:19][C@H:18]2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:31]>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]2[CH2:19][C@H:18]2[N:20]([CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reactant: CN1CCN(C(=O)CCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)CN(C(=O)OC(C)(C)C)[C@@H]2C[C@H]2c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1.5 equiv of NaH in dry DMF (10 vols) at 0° C. was added a solution of ter-butyl(trans)-2-[4-(benzyloxy)phenyl]cyclopropylcarbamate (Intermediate C, 1 equiv) in dry DMF (2 vols) and stirr for 30 mins. Then, added was a solution of 1-(chloroacetyl)-4-methylpiperazine (1.5 equiv) in dry DMF (10 mL) at 0° C., stirred for 1 h at 0° C. to RT. The progress of the reaction was monitored by TLC. After completion, reaction mixture was poured into ice water and extracted with EtOAC. The combined extracts were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purifying by preparative HPLC to get tert-butyl(trans)-2-[4(benzyloxy)phenyl]cyclopropyl(2-(4-methylpiperazin-1-yl)-2-oxoethyl)carbamate derivative.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N+:4]([O-:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:11][O-:12].[Na+].CO>>[Br:1][C:2]1[C:3]([O:12][CH3:11])=[N+:4]([O-:9])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(Cl)[n+]1[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(Br)ccc(C)[n+]1[O-]

Procedure:
step b—A solution of 52a (0.5 g) and 0.5 M NaOMe/MeOH (4.9 mL) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the residue loaded on a SiO2 column and eluted with 5% MeOH/DCM to afford 3-bromo-2-methoxy-6-methyl-pyridine 1-oxide (52b).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: BrCCCCCCBr
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(CCOCCCCCCBr)cc1
Yield: 1851.4 %

Procedure:
4-Nitrobenzeneethanol (10.25 g), 1,6-dibromohexane (27 ml) tetra-n-butylammonium bisulphate (1.7 g) and 12.5M aqueous sodium hydroxide (55 ml) were stirred together for 40 h. The mixture was diluted with water (250 ml), extracted with ER (3×350 ml) and the combined extracts were washed consecutively with water (250 ml) and brine (250 ml), dried and evaporated to give an oil (42.6 g). The oil was purified by FCC eluting with ER-CX (0:100→1:19) to give the title compound as a yellow oil (9.52 g). T.l.c. (ER-CX 1:19) Rf 0.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>CCO.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1cc(N)ccc1Cl
Yield: 560 %

Procedure:
Iron powder (2.5 g, 44.7 mmol) was added portion-wise to a solution of ethyl 2-(2-chloro-5-nitrophenyl)acetate (8 g, 4.68 mmol) and conc. HCl (12 M, 3.9 mL, 46.8 mmol) in EtOH (100 mL). The resultant mixture was heated at 50° C. for 2 h. The mixture was filtered and the filtrate cake was washed with satd. Na2CO3 until pH 8. The filter cake was further washed with EtOAc and the combined filtrates were partitioned between EtOAc and water. The organics were dried over Na2SO4 and concentrated in vacuo to provide ethyl 2-(5-amino-2-chlorophenyl)acetate (5.6 g, 56% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.00 (d, J=8.4 Hz, 1H), 6.50 (s, J=2.8 Hz, 1H), 6.44 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.20 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.56 (s, 2H), 1.15 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(Cl)Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH2:11]([O:18][C:19]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:30]OS(C)(=O)=O)[CH:27]=2)[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([O:18][C:19]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH2:30][N:8]3[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH2:7]3)[CH:27]=2)[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Solvent: O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)CC1
Yield: 47 %

Procedure:
DCM (33 L) and N-methylpiperazine (21.45 L, 193.4 mol) were stirred at 25° C. and the solution from step 8 added over a minimum of 30 mins such that temperature 20-30° C. After stirring the solution for a further 30 mins water (55 L) was added and the organic phase was washed with water (2×55 L). The product was extracted into 0.8M HCl (66 L) and the layers separated. The aqueous phase was washed with DCM (55 L) and then basified with 2M NaOH to pH 10-11 and the product was extracted into EtOAc (2×55 L). The combined organic phase were filtered to remove solids and the evaporated followed by azeotroping with toluene and drying to constant weight to give the title compound, 6.63 kg (47% yield, 98% pure by hplc).
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([C:14](=[O:16])C)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:17].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>ClCCl>[Br:17][C:8]1([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:13]=[CH:12][C:11]([CH:14]=[O:16])=[CH:10][NH:9]1
Reactant: [Br-]
Reactant: CC(=O)c1cnc(Oc2ccccc2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: O=CC1=CNC(Br)(Oc2ccccc2)N=C1
Temperature: 40 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution consisting of 1-(2-phenoxypyrimidin-5-yl)ethanone (Step B, 400 mg, 1.87 mmol) in dichloromethane (14 mL) was added tetrabutylammonium tribromide (990 mg, 2.05 mmol). The reaction mixture was sealed with a screw top and warmed at 40° C. overnight and allowed to cool to room temperature. Hexane (4 mL) was subsequently added. After three hours and little precipitation, additional (150 mg) tetrabutylammonium tribromide was added and the reaction mixture was stirred overnight at room temperature. The pale yellow precipitate that formed was collected on a filter and washed with 1:1 dichloromethane-hexane to afford the title intermediate (375 mg, 68%); Rf 0.43 with 3:1 v/v hexanes-ethyl acetate; MS (ESI+) m/z 295, 293 (M+1, Br isotopes).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[O:20]>CCOCC>[CH3:8][C:6]1[CH:5]=[C:4]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:3]=[C:2]([NH:1][C:31]([NH:30][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:19]([O:18][CH3:17])=[O:20])(=[O:29])=[O:28])=[O:32])[N:7]=1
Reactant: Cc1cc(COC2CCCCO2)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CCOCC
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(COC2CCCCO2)n1
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 3.25 g of the product from Example 3 in 50 ml of ether was added 3.75 g of 2-methoxycarbonylbenzenesulfonyl isocyanate and the mixture was stirred for 3 hours under nitrogen. The precipitated product was filtered and washed with ether to afford 6.0 g of the title compound, m.p. 126°-128°(d).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1CCCCC(Oc2ccccn2)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide, NaH, and 2-fluoropyridine are reacted to give the product after flash chromatography with CH2Cl2-MeOH. LC-MS: 480 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.05 (s, 1H), 8.0 (m, 2H), 7.60 (m, 1H), 7.45 (d, 1H), 6.85 (m, 2H), 6.75 (d, 1H), 6.05 (d, 1H), 5.20 (m, 1H), 4.10 (m, 1H), 3.75 (m, 4H), 3.25 (m, 4H), 2.28 (m, 1H), 2.10 (m, 3H), 1.85 (m, 2H), 1.70 (m, 1H), 1.40–1.60 (m, 3H).