Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH:7]([O:16][Si](C)(C)C)[CH2:8][P:9]([CH2:14][CH3:15])(=[O:13])[O:10]CC)C(=O)C2=CC=CC=C12.[ClH:27]>>[ClH:27].[NH2:5][CH2:6][CH:7]([OH:16])[CH2:8][P:9]([CH2:14][CH3:15])(=[O:10])[OH:13]
Reactant: CCOP(=O)(CC)CC(CN1C(=O)c2ccccc2C1=O)O[Si](C)(C)C
Agent: Cl
Product: CCP(=O)(O)CC(O)CN
Temperature: 25 °C

Procedure:
A solution of 6.4 g of ethyl 3-phthalimido-2-trimethylsilyloxy-propyl(ethyl)phosphinate in 100 ml of concentrated aqueous hydrochloric acid is heated to reflux for 20 hours. After this time the suspension is cooled to room temperature and filtered. The filtrate is evaporated to dryness, the resulting semi-solid is co-evaporated with water (5×50 ml) and absolute ethanol (5×100 ml) and the white solid is dried in high vacuum overnight. Crystallisation from absolute ethanol/acetone affords 3-amino-2-hydroxy-propyl(ethyl)phosphinic acid hydrochloride, m.p. 114-115°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH:5][C:6]=1[Cl:7].CC(C)([O-])C.[K+].[CH2:24]([O:26][CH2:27]Cl)[CH3:25].O>O1CCCC1>[Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]([CH2:27][O:26][CH2:24][CH3:25])[C:6]=1[Cl:7]
Reactant: CCOCCl
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sample of 4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (1.0 g , 0.003 mole) is dissolved in 10 mL of dry tetrahydrofuran. To this solution is added potassium t-butoxide (0.37 g, 0.0033 mole) followed by chloromethyl ethyl ether (0.312 g, 0.0033 mole). The mixture is stirred for about 1 hour at room temperature and then poured into a large volume of water precipitating the product. The white solid is collected and dried to give 1.0 g (91%) with m.p. 128°-130°.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].[N:30]#[C:31]Br>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:21])=[O:22])[CH:17]=[CH:16][C:3]=1[O:4][CH2:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:11][CH2:12][N:13]([C:31]#[N:30])[CH2:14][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)c(F)c1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C#N)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-((1R,2S)-2-{2-{2-fluoro-4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidine (Step C, Example 111; 150 mg, 0.428 mmol) and potassium carbonate (244 mg, 1.77 mmol) were stirred in chloroform (7 mL). Cyanogen bromide (61 mg, 0.58 mmol) was added. The mixture was stirred at RT for 15 min and refluxed overnight. The mixture was cooled to RT, mixed with silica gel (5 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (97.5:2.5, 1 L to provide the title compound as an white solid. MS (Multimode) m/z 367 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:9]=[C:4]3[CH2:3][CH:2]([CH3:1])[CH2:7][NH:6][C:5]3=[N:8][C:18]=2[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[CH:15][CH:16]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Cc1cnc(N)c(N)c1
Product: CC1CNc2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)nc2C1

Procedure:
The title compound was prepared from 5-methylpyridine-2,3-diamine and 1,2-bis(4-fluorophenyl)ethane-1,2-dione analogously to Intermediate E;
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:11]3[N:12]=[CH:13][C:14]([C:15]#[N:16])=[C:10]3[NH:9][C:8]=2[C:17]2[C:26]([O:27][CH3:28])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:29]>CS(C)=O.[Cl-].[Na+].O>[NH2:9][C:10]1[N:11](/[C:7](=[N:6]/[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)/[C:8]([C:17]2[C:26]([O:27][CH3:28])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:29])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: O
Reactant: COc1cc2ccccc2cc1-c1[nH]c2c(C#N)cnn2c1NC1CCCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc2ccccc2cc1C(=O)/C(=N\C1CCCC1)n1ncc(C#N)c1N
Yield: 23 %

Procedure:
A light yellow solution of 3-(cyclopentylamino)-2-(3-methoxynaphthalen-2-yl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (150 mg, 0.404 mmol) in DMSO (6 mL) was stored for 40 days at RT. Then, it was poured into a mixture of water and brine solution (˜150 mL) and the organic compound was extracted into ethyl acetate (2×50 mL). The combined extracts were washed with brine solution and dried over anhydrous MgSO4. Filtration and concentration gave the light yellow oil which was purified using an ISCO (40 g) column chromatography eluting with 0-60% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to isolate 36 mg (23% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(3-methoxynaphthalen-2-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.42-1.64 (br m, 4H), 1.64-1.80 (br, 4H), 3.75 (p, 1H), 3.77 (s, 3H), 7.45 (t, J=2.4 Hz, 1H), 7.48 (s, 1H), 7.64 (s, 1H), 7.65 (t, J=2.4 Hz, 1H) 7.88 (d, 1H), 8.10 (br s, 2H), 8.12 (d, 1H), 8.62 (s, 1H). LC/MS calcd. for C22H21N5O2 (m/e) 387.441, obsd. 388.0 (M+H, ES+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[C:45]([O:44][C:43](=[O:49])[NH:42][C@H:39]1[CH2:38][CH2:37][C@H:36]([NH:35][C:32]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]=3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]=2[CH3:31])=[O:34])[CH2:41][CH2:40]1)([CH3:48])([CH3:46])[CH3:47]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c6) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:27]/[NH:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)(=[O:19])=[O:20])[CH:22]=1)/[CH3:10]
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1Cl
Temperature: 120 °C

Procedure:
1-(2,5-Dichlorophenyl)ethanone (20 mg, 0.106 mmol) and 3-(morpholinosulfonyl)benzohydrazide (30.2 mg, 0.106 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography affording the title compound in a 10 mg yield. 1H NMR (400 MHz, CDCl3): δ 8.29 (m, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 7.57 (m, 1H), 7.40 (m, 1H), 7.26 (m, 2H), 3.52 (m, 4H), 2.91 (m, 4H), 2.28 (s, 3H). ESI-MS: 456.1 [M+H]+.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[S:20][C:19]([CH:21]([CH2:25][C:26]#[N:27])[CH2:22][C:23]#[N:24])=[N:18][CH:17]=3)[C:10]=2[CH:9]=[CH:8]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:12]1[C:11]2[NH:7][CH:8]=[CH:9][C:10]=2[C:15]([C:16]2[S:20][C:19]([CH:21]([CH2:25][C:26]#[N:27])[CH2:22][C:23]#[N:24])=[N:18][CH:17]=2)=[N:14][CH:13]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnc(C(CC#N)CC#N)s3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(CC#N)c1ncc(-c2ncnc3[nH]ccc23)s1
Reaction time: 4 h
Yield: 61.8 %

Procedure:
A solution of 3-[5-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3-thiazol-2-yl]pentanedinitrile (14 mg, 0.033 mmol) in DCM (3 mL) containing TFA (0.6 mL) was stirred for 4 hours. The mixture was then concentrated and the residue was redissolved in methanol (2 mL) to which ethylenediamine (0.4 mL) was then added. After 1 hour reaction time, the product was purified by preparative-HPLC/MS (C18 eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (6 mg, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH2:9]([Sn](CCCC)(CCCC)CCCC)[CH:10]=[CH2:11]>>[CH2:11]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH:10]=[CH2:9]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1ccc(I)cc1
Product: C=CCc1ccc(Br)cc1

Procedure:
In a Stille coupling reaction, 1-bromo-4-iodobenzene and allyltri-n-butyltin were reacted to yield Compound 1. Thus, tetrakistriphenylphosphine palladium(0) (1.976 g, 1.710×10−3 mol) was weighed out in a nitrogen-filled glove box and transferred to a Schlenk line. Allyltri-n-butyltin (10.60 mL, 3.419×10−2 mol) and 1-bromo-4-iodobenzene (9.680 g, 3.422×10−2 mol) were added along with 115 mL distilled, degassed 1,4-dioxane to yield a yellow reaction mixture that darkened to orange as the reaction progressed. The reaction mixture was stirred at 70° C. for 46 h until analysis by TLC (hexanes) and GC/MS showed that reaction was complete. The mixture was next cooled to room temperature, filtered through Celite (rinsing with hexanes), and resulting solution washed with both hexanes and water, to remove PPh3. Then the organic portion was dried over MgSO4. Filtration through Celite and removal of the solvent in a rotary evaporator at <75° C. yielded an orange oil. Column chromatography on silica gel with hexanes as eluant afforded only Compound 1 and tri-n-butyltin iodide. These were separated via vacuum distillation at 160 mTorr, where Compound 1 distills at about 50° C. (never exceed 75° C., which can potentially cause allyl group isomerization) as a clear colorless oil (2.810 g, 42% yield). GC/MS: single peak; m/z (rel. intensity) 198 (M+, 46), 196 (M+, 46), 117 (100), 115 (86). 1H NMR (CDCl3): δ7.41 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 5.90 (m, 1H), 5.09 (m, 2H), 3.36 (d, J=7.0 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8]
Reactant: C=CCOC(=O)c1cccc([N+](=O)[O-])c1
Solvent: CO
Product: C=CCOC(=O)c1cccc(N)c1

Procedure:
Reduction of the above nitro compound by the method of Example 2, except that the solvent was methanol, gave allyl 3-aminobenzoate. Nmr (CDCl3): δ 3.38 (br, 2H); 4.79 (dt, 2H); 5.24-5.44 (m, 2H); 5.93-6.09 (m, 1H); 6.86 (dm, 1H); 7.21 (t, 1H); 7.37 (t, 1H); 7.45 (dt, 1H).
Reaction SMILES: [CH:1]([S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)SC1C=CC=CC=1.[Sn](Cl)(Cl)(Cl)Cl.[C:28]1([O:38][Si](C)(C)C)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH:29]=1>ClCCl>[C:17]1([S:16][CH:1]([S:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:29]2[CH2:30][CH2:31][C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]2=[O:38])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(SC(Sc2ccccc2)Sc2ccccc2)cc1
Reactant: C[Si](C)(C)OC1=CCCc2ccccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C1c2ccccc2CCC1C(Sc1ccccc1)Sc1ccccc1
Temperature: -70 °C
Reaction time: 0.67 h
Yield: 64.7 %

Procedure:
Under argon, 6.22 g (23.8 mmol) of triphenyl trithioorthoformate (1,1′,1″-(methanetriyltrisulphanediyl)dibenzene) are dissolved in anhydrous dichloromethane and cooled to −70° C. 23.8 ml (23.8 mmol) of tin(IV) tetrachloride solution (1 M in dichloromethane) and 5.73 g (26.3 mmol) of (3,4-dihydronaphthalen-1-yloxy)trimethylsilane are added in succession, and the mixture is stirred at −70° C. for 40 min. The reaction mixture is poured into ice-water and extracted with dichloromethane. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate) gives 5.80 g of 2-[bis(phenylsulphanyl)methyl]-3,4-dihydronaphthalen-1(2H)-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)=[O:16].[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:30]2[CH2:31][CH2:32][N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CC(C)N1CCNCC1
Reactant: O=C(NCCCCCCCCCCCCO)c1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
To 2.78 g of N-(12-hydroxydodecyl)-6-chloropyridine-3-carboxamide was added 4.15 g of 1-isopropylpiperazine and the mixture was stirred at 160° C. for 30 minutes. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and distilled off under reduced pressure. The residue was chromatographed over a silica gel column to afford 2.2 g of the title compound as a crystal.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13](=[O:15])[CH3:14])=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Cc1ccc(F)cc1
Product: CC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: -35 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
Treat a −35° C. solution of fuming nitric acid (32.3 mL, 723 mmol) with 4-fluorophenylacetone (1.756 ml, 13.14 mmol) and stir at −35° C. for 1 h. Pour the mixture onto ice, extract with DCM (2×), dry the combined organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (1.07 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 7.97 (dd, J=7.4, 2.2 Hz, 1H), 7.58 (ddd, J=8.6, 4.6, 2.2 Hz, 1H), 7.52 (dd, J=11.3, 8.6 Hz, 1H), 3.95 (s, 2H), 2.17 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH2:20].[OH-].[Na+].OO>C1COCC1>[OH:20][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C:2]([CH3:1])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC=CC1(C)c1ccccc1
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)CC1(C)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 20-4 (0.50 g, 1.9 mmol) in anhydrous THF (80 mL) at 0° C. was treated with BH3:THF (1.93 mL, 1.9 mmol) then stirred for 1 hour. at 25° C. Water (0.35 mL, 19.2 mmol) was added, followed by 3 N NaOH (0.23 mL, 5.8 mmol). The resulting solution was cooled to 0° C. prior to the addition of 30% H2O2 (0.22 mL, 1.9 mmol). The reaction was partitioned between sat. aq. NaHCO3 (100 mL) and EtOAc (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column (SiO2, O-100% EtOAc/Hexanes gradient) to yield tert-butyl 4-hydroxy-2-methyl-2-phenylpyrrolidine-1-carboxylate, 20-5: LRMS m/z (M+H) 278.2 found, 278.1 required.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C)[CH2:13][CH2:12]3)=[N:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C1(C)C=CC=CC=1>O>[C:28]1([O:27][C:25]([N:14]2[CH2:13][CH2:12][CH:11]([C:8]3[C:7]4[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=4[O:10][N:9]=3)[CH2:16][CH2:15]2)=[O:26])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1CCC(c2noc3cccc(F)c23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)N1CCC(c2noc3cccc(F)c23)CC1
Yield: 63.3 %

Procedure:
A mixture of 1.74 g of 4-fluoro-3-(1-methyl-4-piperidyl)-1,2-benzisoxazole, 1.25 g of potassium carbonate, 1.40 g of phenyl chloroformate and 50.0 ml of toluene was stirred under reflux for 8.0 hrs. The mixture was poured into water and the toluene layer was separated, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was purified by passing through a silica gel column (20:1), using 1% methanol in dichloromethane as the eluent. The eluent was evaporated and the residue solidified when scratched to yield a solid. The solid was recrystallized from petroleum-ether (bp 30°-60°) to yield 1.6 g (64%) of product, mp 108°-110°.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH3:12])=[N:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[C:16]([O:15][C:13]([N:10]([CH2:11][CH3:12])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][N:6]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)OC)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The crude 6-(tert-butoxycarbonyl-ethyl-amino)-nicotinic acid methyl ester is taken up in 100 mL dioxane and a solution of lithium hydroxide monohydrate (13.5 g, 0.32 mol) in 100 mL water is added and the reaction mixture is stirred at RT for 4 h. The dioxane is removed from the reaction mixture under reduced pressure, additional water is added and the reaction mixture is acidified to pH 6 with a solution of 10% citric acid in water. The formed precipitate is filtered off and dried in vacuo. Yield: 36 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][CH:13]=O)[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1.[F:23][CH:24]1[CH2:27][NH:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH:7]([CH2:12][CH2:13][N:26]3[CH2:27][CH:24]([F:23])[CH2:25]3)[N:6]3[C:15]4[CH:16]=[CH:17][CH:18]=[C:19]([F:22])[C:20]=4[CH:21]=[C:5]3[C:4]=2[N:3]=1
Reactant: FC1CNC1
Reactant: O=CCC1Cc2ccc(Cl)nc2-c2cc3c(F)cccc3n21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cccc2c1cc1n2C(CCN2CC(F)C2)Cc2ccc(Cl)nc2-1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
A mixture of 2-(2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridin-6-yl)acetaldehyde (200 mg, 0.617 mmol) and 3-fluoroazetidine (95 mg, 1.23 mmol) in DCM (4 mL) was stirred at room temperature for 30 minutes under N2. Then Na(OAc)3BH (50 mg) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. After dilution with water (30 mL) and extraction with EA (20 mL×3), the organic layer was washed with brine (30 mL*3), dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EA=1:1) to afford the desired product of 2-chloro-11-fluoro-6-(2-(3-fluoroazetidin-1-yl)ethyl)-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (100 mg, yield: 43%). 1H-NMR (CDCl3, 400 MHz) δ 7.44 (d, J=8.0 Hz, 1H), 7.3 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.10 (t, J=4.8 Hz, J=2.7 Hz, 2H), 6.69˜6.74 (m, 1H), 5.11˜5.14 (m, 0.5H), 4.97˜4.50 (m, 0.5H), 4.87 (t, J=4.8 Hz, 1H), 3.57 (d, J=6.8 Hz, 1H), 3.33˜3.39 (m, 1H), 2.95˜3.06 (m, 2H), 2.2˜72.38 (m, 1H). MS (M+H)+: 374/376.
Reaction SMILES: CO.[Cl:3][C:4]1[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[CH:15]=[O:16])=[N:6][CH:7]=[CH:8][CH:9]=1.[S-:17][C:18]#[N:19].[Na+].BrBr>[Br-].[Na+].CO>[Cl:3][C:4]1[C:5]([N:10]2[C:14]([S:17][C:18]#[N:19])=[CH:13][CH:12]=[C:11]2[CH:15]=[O:16])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#C[S-]
Reactant: O=Cc1cccn1-c1ncccc1Cl
Agent: BrBr
Agent: [Br-]
Agent: [Na+]
Solvent: CO
Product: N#CSc1ccc(C=O)n1-c1ncccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.4 %

Procedure:
To 10 ml of methanol were added 1.0 g of 3-chloro-2-(2-formyl-1H-pyrrol-1-yl)pyridine and 1.4 g of sodium thiocyanate. A solution of 1.0 g of bromine in 5 ml of saturated sodium bromide-methanol was added dropwise thereto at −20° C. The resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was added to 100 ml of ice water, and extracted with chloroform two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 1.6 g of 1-(3-chloro-2-pyridinyl)-5-thiocyanato-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(Cl)c12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1c(Cl)nn2CCN1CCCC1
Temperature: 50 °C

Procedure:
A mixture of 3-chloro-4-nitro-1H-indazole (0.550 g, 2.79 mmol) was treated with potassium carbonate (1.20 g 8.70 mmol) in DMF (10 mL) for 30 minutes, after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (0.710 g, 4.20 mmol) was added. The mixture was heated to 50° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The combined filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (m, 4H), 2.46 (m, 4H), 2.90 (t, 2H, J=6.44), 4.61 (t, 2H, J=6.44), 7.66 (m, 1H), 7.98 (m, 1H), 8.25 (m, 1H); MS (DCI/NH3) m/z 261 [M+H]+.