Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN1CCCCC1.[C:9]1([C:15]([NH:28][CH:29]2[C:39](=[O:40])[N:31]3[CH:32]([C:37]#[N:38])[C:33]([CH3:36])([CH3:35])[S:34][C@H:30]23)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N-:41]=[N+:42]=[N-:43].[Na+].CN1CCCCC1>C(Cl)(Cl)Cl.O.C(O)C>[C:9]1([C:15]([NH:28][CH:29]2[C:39](=[O:40])[N:31]3[CH:32]([C:37]4[NH:43][N:42]=[N:41][N:38]=4)[C:33]([CH3:36])([CH3:35])[S:34][C@H:30]23)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN1CCCCC1
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 53 °C

Procedure:
A mixture of dry N-methylpiperidine hydrochloride (8.14 g., 0.06 mole) anhydrous ethanol free chloroform (180 ml.), 6-triphenylmethylamino-2,2-dimethyl-3-cyanopenam (13.2g, 0.03 mole), finely powdered sodium azide (3.9 g., 0.06 mole) and N-methylpiperidine (8.9 g., 0.09 mole) is heated to 53° C. (internal temperature) for 80 minutes. It is then cooled to room temperature and diluted with ethanolfree chloroform (750 ml.) and water (800 ml.). It is thoroughly shaken, thechloroform phase separated and washed successively with 1.5N HCl (1 ×1000 ml.) and water (1 × 800 ml.). The chloroform solution is filtered through anhydrous sodium sulfate and then concentrated under reduced pressure to about 300 ml. White crystals separate. The concentrateis diluted with hexane (350 ml.) and filtered after 15 minutes. The crystalline product is washed with hexane and dried in air for 15 minutes followed by drying under vacuum at 56° C. for 1 hour. Yield = 7.66 g. (52.9%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[N:12][OH:13])[CH3:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][N:12]=[C:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[OH:1])[CH3:11])(=[O:16])[CH3:15]
Reactant: COc1ccc(O)c(C(C)=NO)c1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(O)c(C(C)=NOC(C)=O)c1
Temperature: 50 °C

Procedure:
A mixture of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone oxime (13.7 g, 0.076 mol.) and acetic anhydride (50 mL) was heated at 50° C. for 10 min. The mixture was cooled to 0° C., filtered, and the filtrant washed with water (50 mL) and dried to give 15.5 g solid. MS (m/e): 224 (M++1), 164 (100).
Reaction SMILES: C(=[N:14][CH:15]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1)[C:16]#[N:17])(C1C=CC=CC=1)C1C=CC=CC=1.Cl>O1CCOCC1>[NH2:14][CH:15]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1)[C:16]#[N:17]
Reactant: N#CC(Cc1ccnc2ccccc12)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC(N)Cc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
To 2-(Benzhydrylideneamino)-3-quinolin-4-yl-propionitrile (0.155 g, 4.29 mmol) in 5 ml dioxane, 1N HCl (1.3 ml, 12.8 mmol) was added and the reaction mixture stirred at room temperature overnight. The solution was concentrated under reduced pressure, partitioned between 10 ml water and EtOAc (10 ml). The organic layer was dried over sodium sulfate filtered and concentrated to give 2-Amino-3-quinolin-4-yl-propionitrile 0.036 g (43%) which was used as such for the subsequent step.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[OH:7][C@@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C:22]2=[CH:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=O)[CH2:9]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[OH:7][C@@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C:22]2=[CH:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16]/[C:17]/2=[CH:1]/[CH3:2])[CH2:9]1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)C3=CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of potassium tert-butoxide in THF (1 M, 230 mL, 231 mmol) was added drop wise to a suspension of ethyltriphenylphosphonium bromide (88.7 g, 239 mmol) in THF (150 mL) over 1 h at 25° C. The resulting dark red colored mixture was stirred for an additional 1 h at 25° C. A solution of compound 1.3 (23.0 g, 79.7 mmol) in THF (230 mL) was added slowly to the red-colored mixture at 25° C. The resulting mixture was stirred for 3-4 h, at which point it was determined to be complete by TLC. The reaction was quenched by adding saturated aqueous NH4Cl solution (75 mL). The phases were separated and the aqueous layer was extracted three times with EtOAc (3×150 mL). The organic fractions were combined, washed with saturated brine solution (100 mL), dried over Na2SO4 (75 g), and filtered. The filtrate was concentrated under vacuum and the crude solid was purified by column chromatography [49 mm (W)×600 mm (L), 60-120 mesh silica, 300 g] eluting with ethyl acetate/hexanes (1:9). The fractions containing product were combined and concentrated, providing compound 1.5 (19.1 g, 80.0%) as a white solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22](=O)[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]([S@@:29]([NH2:31])=[O:30])([CH3:28])[CH3:27].C(Cl)Cl>[Cl-].[Na+].O>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17](/[C:22](=[N:31]\[S@@:29]([C:26]([CH3:28])([CH3:27])[CH3:25])=[O:30])/[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(=O)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C/C(=N/[S@](=O)C(C)(C)C)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 25 °C

Procedure:
To the solution of 1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethanone (0.2227 g, 0.0006843 mol) and (s)-(−)-2-Methyl-2-propanesulfinamide (0.0829 g, 0.000684 mol) in Methylene chloride (1.4 mL, 0.021 mol) was added Ti(OEt)4 (0.488 mL, 0.00171 mol). The reaction was stirred at room temperature for id. The mixture was then cooled to 0° C., added equal volume brine, filtrate through celite, and extracted with EtOAc. After died over Na2SO4, the residue was chromatographed 0-50% EA/HE gave product (132 mg, 45%). LCMS 2.39 min m/z 429.30 ([M+1], 100%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:9]=[C:8]([O:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1F
Product: COc1ccc(Oc2ccc(C=O)c(F)c2)cc1

Procedure:
Analogously to Example (40a) 2,4-difluorobenzaldehyde and 4-methoxyphenol were used as starting material.
Reaction SMILES: [C:1]([OH:16])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[C:1]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCC(=O)Nc1ccccc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
A three liter flask equipped with a stirrer, theremometer, nitrogen inlet, Barrett trap and condenser was used. Myristic acid (commercially available from Emery Chemicals, 97 percent purity, 685 grams, 3.0 moles), aniline (300 ml., 3.2 moles) and 120 ml xylene were charged to the flask. The mixture was stirred and heated for approximately 61/2 hours at a temperature of from about 170° C.-220° C. The reaction was conducted in a nitrogen atmosphere. The reaction mixture was then cooled to 140° C. and poured into a 4 liter beaker. About 1.8 liters of denatured alcohol were slowly added to the reaction solution. After standing overnight, the slurry of semi-solid myristanilide was collected by filtration. The filter cake was washed thoroughly with two portions of denatured alcohol and then air dried at about 22° C. The resultant white crystalline solid weighed 706 grams and had a melting point of 83.5° C.-84.5° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][S:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:33]=2)[CH2:26][CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=[CH:19][C:18]1=2>ClCCl>[CH3:8][S:9]([O:13][CH2:14][CH2:15][S:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:33]=2)[C:18]2[C:23](=[CH:22][C:21]([C:27]#[N:28])=[CH:20][CH:19]=2)[CH2:24][CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc2c(c1)CCCC2(SCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 mmol of triethylamine and 2 mmol of methanesulphonyl chloride are added to a solution of 1 mmol of 5-(2-hydroxyethylsulphanyl)-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloromethane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is identified on the basis of the Rf and used without further purification in the next stage.
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[O:11][C:10]([CH3:12])=[N:9][C:8]=1[C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[CH:14]=1)[C:3]([OH:5])=[O:4]>C(O)(=O)C.[Zn]>[CH3:12][C:10]1[O:11][C:7]([CH2:6][CH2:2][C:3]([OH:5])=[O:4])=[C:8]([C:13]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=2)[N:9]=1
Reactant: Cc1nc(-c2ccc3c(c2)CCCC3)c(CC(Cl)C(=O)O)o1
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc3c(c2)CCCC3)c(CCC(=O)O)o1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a solution of 2-chloro-3-[2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]propionic acid (3.2 g) in acetic acid (30 mL) was added zinc powder (3.25 g) at 90° C. and the mixture was stirred at 90° C. for 15 min. The insoluble material was removed by filtration and the filtrate was concentrated. Water was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 3-[2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]propionic acid (2.25 g, yield 79%) as colorless prism crystals. melting point: 135–136° C.
Reaction SMILES: [C:1](=[O:10])([O:5][CH2:6][CH2:7][O:8][CH3:9])[O:2][CH2:3]I.[Na].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH2:20][NH:21][C:22]([C:24]1[C:25](=[O:41])[C:26]([OH:40])=[C:27]2[C:36](=[O:37])[N:35]3[C@@H:30]([O:31][CH2:32][CH2:33][C@H:34]3[CH3:38])[CH2:29][N:28]2[CH:39]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1](=[O:10])([O:5][CH2:6][CH2:7][O:8][CH3:9])[O:2][CH2:3][O:40][C:26]1[C:25](=[O:41])[C:24]([C:22]([NH:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[O:23])=[CH:39][N:28]2[C:27]=1[C:36](=[O:37])[N:35]1[C@@H:30]([O:31][CH2:32][CH2:33][C@H:34]1[CH3:38])[CH2:29]2
Reactant: C[C@@H]1CCO[C@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(O)c3C(=O)N12
Reactant: COCCOC(=O)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Product: COCCOC(=O)OCOc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@@H]1OCC[C@@H](C)N1C2=O

Procedure:
The title compound was prepared from iodomethyl 2-(methyloxy)ethyl carbonate (59 mg, 0.227 mmol) (prepared in a similar manner to example 1), (4R,12aS)-N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide sodium salt (50 mg, 0.113 mmol), potassium carbonate (47 mg, 0.340 mmol), and tetrabutylammonium hydrogen sulfate (39 mg, 0.113 mmol), using a similar process to that described in example 1. 1H NMR (CDCl3) δ 10.32 (m, 1H), 8.37 (s, 1H), 7.31 (m, 1H), 6.77 (m, 2H), 5.83 (m, 2H), 5.16 (m, 1H), 4.92 (m, 1H), 4.57 (d, J=6 Hz, 2H), 4.29-4.23 (m, 3H), 4.16 (m, 1H), 3.93 (m, 2H), 3.62-3.57 (m, 2H), 3.32 (s, 3H), 2.13 (m, 1H), 1.46 (m, 1H), 1.30 (d, J=7.2 Hz, 3 H). ES+MS: 552 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:9]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Brc1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A solution of 4-bromoaniline (1.76 g, 10 mmol) and benzaldehyde (1.06 g, 10 mmol) in dichloroethane (15 mL) was treated with NaBH(OAc)3 (2.32 g, 11 mmol) and glacial acetic acid (1 mL), stirred overnight at room temperature, quenched with 1N NaOH, and extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with water and brine, dried, (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5:1 hexanes/ethyl acetate to provide 2.21 g (84%) of the desired product. MS(ESI) m/e 261.9 (M+H)+, 263.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].[Al+3].[Cl-].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].O>C[N+]([O-])=O>[Cl:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([C:15](=[O:17])[CH3:16])[CH:7]=1
Reactant: COc1ccc(Cl)c(F)c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Product: COc1cc(F)c(Cl)cc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a stirred solution of DMF (10 mL) and 4-chloro-3-fluorophenol (1 g, 6.84 mmol) at RT, K2CO3 (1.4 g, 10.3 mmol) was added and solution was allowed to stir at room temperature for additional 15 min. Methyl iodide (1.16 g, 8.21 mmol) was added to the mixture and mixture was allowed to stir for overnight at RT. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. 1-chloro-2-fluoro-4-methoxybenzene was obtained via column chromatography (10/1 Hexanes/Ethyl acetate). To a stirred solution of 1-chloro-2-fluoro-4-methoxybenzene (1.09 g, 6.82 mmol) and AlCl3 (1.36 g, 10.23 mmol) in CH3NO2 at 0° C., acetyl chloride (0.80 g, 10.23 mmol) was added and solution was allowed to warm up to room temperature and stir for overnight. After the completion of reaction 10 mL of water was added and was extracted with ethyl acetate (3×15 mL) and the resulting organic layer was washed with water, brine and dried. The solvent was removed in vacuo. The crude was purified by flash column chromatography using 10/1 Hexanes/Ethyl acetate to afford product (46%). 1H NMR: 2.59 (s, 3H), 3.91 (s, 3H), 6.78 (d, 1H, J=10.5 Hz), 7.85 (d, 1H, J=8.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[N:11](C(OC(C)(C)C)=O)[C:10]1[C:9](=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][C:14]=1[Cl:15])[NH:11][C:10]1[C:9](=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: CC(C)(C)OC(=O)n1c2c(c3cc(Cl)c(Cl)cc31)CCCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl 6,7-dichloro-1-oxo-3,4-dihydro-1H-carbazole-9(2H)-carboxylate (1.4 g, 3.9 mmol) in DCM (20 mL), cooled to 0° C., was added TFA (2 mL). The reaction mixture was stirred at 0° C. for 1 h, neutralized with saturated NaHCO3 (15 mL) and extracted with DCM (2×15 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a white solid (850 mg, 85%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.87 (bs, 1H), 7.75 (s, 1H), 7.55 (s, 1H), 2.98 (t, J=6.0 Hz, 2H), 2.68 (t, J=6.0 Hz, 2H), 2.30-2.25 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.N1C=CC=CC=1.Cl>O>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1
Reactant: NCCCN
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: NCCCNc1ccc(Br)cn1

Procedure:
A mixture of 1,3-diaminopropane (17.6 ml), 2,5-dibromopyridine (10 g) and pyridine (5 ml) was heated under reflux for 4 hr. After stripping off the excess of 1,3-diaminopropane, the residue was taken up in water, the pH adjusted to 7 (conc. hydrochloric acid) and the solution extracted with chloroform. The pH was raised to 14 and extracted with chloroform. After drying (K2CO3), the final extract was evaporated to give 2-(3-aminopropylamino)-5-bromopyridine (9.1 g) as an oil which was used without further purification. (ii) To a suspension of sodium hydride (0.3 g) in DMSO (20 ml) was added 2-(3-aminopropylamino)-5-bromopyridine (2.88 g). The mixture was stirred and heated slowly to 85° C. After the evolution of hydrogen had ceased the mixture was cooled to room temperature and methyl iodide (1.77 g) in DMSO (5 ml) added dropwise maintaining the temperature below 30° C. After a further 15 min water (150 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with water and extracted with 1N hydrochloric acid. The acid extract was washed with chloroform, the pH adjusted to 13 (2N NaOH) and extracted again with chloroform. The final extract was stripped and the residue chromatographed (silica gel, 5% ammoniacal methanol/dichloromethane) to give 2-[N-(3-aminopropyl)-N-methylamino]-5-bromopyridine (1.44 g) as an oil which was used without further purification. (iii) 2-[N-(3-aminopropyl)-N-methylamino]-5-bromopyridine (1.4 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.25 g) were heated together under reflux in pyridine (10 ml) for 20 hr. After stripping, the residue was triturated with wet ether and recrystallised from isopropanol/water to give 2-[3-[N-methyl-N-(5-bromopyrimid-2-yl)amino]propylamino]-5-(6-methylpyrid-3-yl-methyl)pyrimid-4-one, 1.5 g (71%) mp 137°-40° C.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]([NH:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)NCC1CCC(N)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
Isopropyl iodide (2 equivalents) was added dropwise to a suspension of tert-butyl N-[4-aminocyclohexyl]methyl-carbamate (1 equivalent) and diisopropylethyl amine (3 equivalents) in THF. The resulting mixture was stirred for 1 day. TLC analysis showed some starting amine. Additional isopropyl iodide (1 equivalent) and diisopropylethyl amine (3 equivalents) were added to the reaction mixture and heated at 40° C. for 1 day. The reaction mixture was concentrated and chromatrographed to give tert-butyl N-[4-(isopropylamino)cyclohexyl]methylcarbamate: 22% yield, 271 (ESMS, MH+); 1H NMR (CDCl3) δ 4.65 (broad, 1H), 2.91 (m, 3H), 2.42 (m, 1H), 1.80 (ABm, 4H), 1.38 (s, 9H), 0.98 (d, 6H, J=6.3 Hz), 1.32–0.85 (m, 5H).
Reaction SMILES: [Br:1]C1C(C)=NC(C2C=CC(Cl)=CC=2Cl)=C(C)N=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:26]1[C:27]([CH2:35][CH3:36])=[N+:28]([O-])[CH:29]=[C:30]([CH2:32][CH3:33])[N:31]=1>>[Br:1][C:29]1[C:30]([CH2:32][CH3:33])=[N:31][C:26]([C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[Cl:18])=[C:27]([CH2:35][CH3:36])[N:28]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2Cl)c(C)nc1Br
Reactant: CCc1c[n+]([O-])c(CC)c(-c2ccc(Cl)cc2Cl)n1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1Br

Procedure:
Following the procedure of 2-bromo-5-(2,4-dichlorophenyl)-3,6-dimethylpyrazine but substituting 3-(2,4-dichlorophenyl)-2,5-diethylpyrazine 1-oxide and making non-critical variations provided the title compound as an oil: 1H NMR (CDCl3) δ 1.19 7.5, 1.33, 2.63, 3.02, 7.28, 7.39, 7.54; MS (ESI+) for C14H13Br1Cl2N2 m/z 361.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]3)[C:6]=2[N:21]=1.[H-].[Na+].[CH3:24]I.Cl>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:24])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16]3)[C:6]=2[N:21]=1
Reactant: C[C@@H]1CCC(N2CC(F)(F)C(=O)Nc3cnc(Cl)nc32)C1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: C[C@@H]1CCC(N2CC(F)(F)C(=O)N(C)c3cnc(Cl)nc32)C1
Reaction time: 0.5 h

Procedure:
2-Chloro-7,7-difluoro-9-((3R)-3-methylcyclopentyl)-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one was methylated on 5-position using sodium hydride and methyl iodide. After 30 minutes the reaction was deemed complete by LCMS, poured into ice, the solution acidified with 1N HCl, the product filtered off as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91-2.22 (m, 10H) 3.34 (s, 3H) 4.04-4.35 (m, 2H) 4.72-5.04 (m, 1H) 8.35 (s, 1H). m/z 331.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](S(C1C=CC=CC=1)(=O)=O)[CH2:7][CH2:6]2)[CH3:2].[OH-].[Na+]>Br>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2)[CH3:2]
Reactant: CCc1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CCc1ccc2c(c1)CCN2
Yield: 34 %

Procedure:
A mixture of 5-ethyl-1-(phenylsulfonyl)indoline (15 g, 0.050 mol) in HBr (48%, 162 mL) was heated at reflux for 6 h. The mixture was basified with sat. NaOH to pH 9 and then it was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica column to give 5-ethylindoline (2.5 g, 32%).