Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O-])(=[S:13])[CH3:12].[K+]>CC(C)=O>[C:11]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])(=[S:13])[CH3:12]
Reactant: O=C(CCl)c1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=S)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroacetophenone in acetone (3.10 g, 200 ml) was added potassium thioacetate (2.80 g, 1.2 equivalents) and the reaction mixture was stirred overnight at RT. The salt precipitate was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel to give 2.04 g of α-thioacetyl acetophenone as orange reddish oil. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 7.98–8.02 (2 H, m) 7.60 (1 H, t, J=7.48 Hz) 7.48 (2 H, t, J=7.78 Hz) 4.40 (2 H, s) 2.41 (3 H, s). MS [ESI, MNa+] m/z calcd for C10H10O2SNa 217.04, found 217.16.
Reaction SMILES: [Na].[C:2]([CH2:4][C:5](OCC)=[O:6])#[N:3].FS(O)(=O)=O.[CH:15]1([C:21]([NH2:23])=[NH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[NH2:3][C:2]1[N:22]=[C:21]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[NH:23][C:5](=[O:6])[CH:4]=1
Reactant: N=C(N)C1CCCCC1
Reactant: CCOC(=O)CC#N
Agent: O=S(=O)(O)F
Agent: [Na]
Solvent: CCO
Product: Nc1cc(=O)[nH]c(C2CCCCC2)n1
Temperature: 0 °C

Procedure:
To a stirred solution of sodium (8.0 g.) in dry ethanol (150 ml.) was added ethyl cyanoacetate (12 ml.) followed after 15 minutes by crude cyclohexanecarboxamidine fluorosulphonate (10 g.). The mixture was heated under reflux for 20 hours, evaporated to half volume, water (100 ml.) was added and the pH adjusted to 6 by the addition of glacial acetic acid. After cooling to 0° C, the solid was filtered off and washed with water and acetone to give 4-amino-2-cyclohexylpyrimid-6-one (18 g.), m.p. 274°-276° C. (with decomposition).
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[C:26]([C:30]4[CH:31]=[CH:32][C:33](=[O:36])[NH:34][N:35]=4)[CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCOc1cccc(-c2ccc(=O)[nH]n2)c1
Product: O=c1ccc(-c2cccc(OCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)c2)n[nH]1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]#[C:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)CCC.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(O[C:41]1[CH:46]=[CH:45][N:44](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:43](=[O:66])[N:42]=1)(=O)=O)(C)C>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:8]1([C:7]#[C:6][C:41]2[CH:46]=[CH:45][NH:44][C:43](=[O:66])[N:42]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Oc2ccn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(=O)n2)c(C(C)C)c1
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=c1nc(C#Cc2ccccc2)cc[nH]1
Temperature: 55 °C

Procedure:
Tributyl(phenylethynyl)stannane (315 mg, 0.8 mmol) was added to a stirred solution of 2-oxo-1-trityl-1,2-dihydropyrimidin-4-yl 2,4,6-triisopropylbenzenesulfonate Part A (200 mg, 0.3 mmol), copper (I) iodide (18.4 mg, 0.1 mmol) and palladium tetrakis (55.8 mg, 0.05 mmol) in 5 mL DMF under nitrogen. The reaction mixture was heated at 55° C. for 16 h, concentrated and subjected to flash chromatography (silica gel/methylene chloride to 15% MeOH-methylene chloride gradient to afford 4-(phenylethynyl)pyrimidin-2(1H)-one 4B (66 mg) as a brownish solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:12][CH:13]=[C:5]([C:6]=23)[CH2:4][N:3]1[CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[NH:17]1[CH2:16][CH2:15][CH:14]([N:3]2[CH2:4][C:5]3=[CH:13][NH:12][C:7]4[C:6]3=[C:11]([CH:10]=[CH:9][N:8]=4)[C:2]2=[O:1])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c[nH]c4nccc(c34)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2ccnc3[nH]cc(c23)CN1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.8 %

Procedure:
tert-Butyl 4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate (18 mg, 0.051 mmol) was dissolved in TFA (1 mL) and DCM (2 mL) and allowed to stir at room temperature for 15 min. The mixture was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 12 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.71-8.72 (s, 1H), 8.42 (d, 1H, J=8.4 Hz), 7.62 (s, 1H), 7.48-7.49 (m, 2H), 5.02 (s, 1H), 4.69-4.75 (m, 2H), 3.58-3.61 (m, 2H), 3.19-3.26 (m, 2H), 2.33-2.39 (m, 2H), 2.10-2.15 (m, 2H). [M+H] found 257.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][C:10]2([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>>[N+:24]([C:23]1[C:18]([N:13]2[CH2:14][CH2:15][C:10]([CH2:9][C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([OH:16])[CH2:11][CH2:12]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: OC1(CC#Cc2ccccc2)CCNCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1N1CCC(O)(CC#Cc2ccccc2)CC1
Yield: 99.5 %

Procedure:
A well homogenised mixture of the Compound 256c (115 mg, 0.53 mmol), 2-chloro-3-nitropyridine (93.1 mg, 0.587 mmol) and triethyl amine (0.092 mL, 0.641 mmol) was stirred at 25° C. for 24 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether 8:2) affording the title product (178 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][C@H:24]1[O:30][C:31](=[O:33])[CH3:32].[N:34]#CBr.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19][CH3:20])[CH:13]=[C:12]([O:21][CH3:22])[C:11]=2[C@@H:23]1[CH2:28][CH2:27][N:26]([C:29]#[N:34])[CH2:25][C@H:24]1[O:30][C:31](=[O:33])[CH3:32]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)C[C@H]1OC(C)=O
Reactant: N#CBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C#N)C[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To compound of example 126 (2.9 g, 6.15 mmol) in dry CHCl3 (40 mL) at 0° C. was added cyanogen bromide (2.1 g, 19.8 mmol). The reaction mixture was stirred at room temperature for 8 h. It was poured into water (100 mL) and extracted with CHCl3 (3×100 mL). The organic extract was washed with water, dried (anhydrous Na2SO4) and concentrated. The solid residue obtained was purified using a silica gel column and 2% IPA+1% liquor NH3 in CHCl3 as eluant to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:17]2[S:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:17]2[S:18][C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]([CH3:22])[N:21]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)c([N+](=O)[O-])c2)nc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)c(N)c2)nc1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.9 %

Procedure:
A reaction mixture solution prepared by suspending 1.14 g of ethyl 2-(3-nitro-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate in 15 mL of ethanol and adding 300 mg of palladium/carbon (10 wt %) was stirred at room temperature for 14 hours under a hydrogen atmosphere. The reaction mixture solution was celite-filtered and the filtrate was concentrated under reduced pressure to obtain 1.05 g of ethyl 2-(3-amino-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:13][CH:12]([OH:14])[CH:11]([OH:15])[CH2:10]1.CCN(C(C)C)C(C)C.[N:25]1([C:31]([NH:33][C@@H:34]([CH2:38][S:39]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)(=[O:41])=[O:40])[C:35](O)=[O:36])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:15][CH:11]1[CH:12]([OH:14])[CH2:13][CH:9]([NH:8][C:35]([C@@H:34]([NH:33][C:31]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:32])[CH2:38][S:39]([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)(=[O:41])=[O:40])=[O:36])[CH2:10]1
Reactant: O=C(O)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: NC1CC(O)C(O)C1
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: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(NC1CC(O)C(O)C1)[C@H](CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.2 %

Procedure:
A solution of 4-amino-cyclopentane-1,2-diol; compound with trifluoroacetic acid (745 mg, 3.23 mmol) in DMF (15 ml) was treated with DIPEA (1.12 ml, 6.4 mmol) and the mixture was stirred for 5 minutes at room temperature. Then (R)-2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (1.15 g, 3.23 mmol) was added followed by HATU (1.23 g, 3.24 mmol). This mixture was stirred at room temperature overnight and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate and then with a mixture of ethyl acetate and methanol to give morpholine-4-carboxylic acid [(R)-1-(3,4-dihydroxy-cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide as a brown solid (680 mg). LC/MS: RT=2.64 min. (215 and 254 nM), MH+=456.
Reaction SMILES: C([Li])CCC.C[Si]([C:10]([Si](C)(C)C)([C:14]([O-:16])=O)[C:11]([O-:13])=[O:12])(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])C(Cl)=O.C(=O)(O)[O-].[Na+].S(=O)(=O)(O)O>C1CCCCC1.CCOCC>[O:16]=[C:14]([C:25]1[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: C[Si](C)(C)C(C(=O)[O-])(C(=O)[O-])[Si](C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCOCC
Product: COc1cc(C(=O)CC(=O)O)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
10 ml of 2M solution of n-butyllithium in cyclohexane was added dropwise over 10 minutes to a stirred solution of 5.08 g (20 mmol) of bis(trimethylsilyl)malonate in 40 ml of anhydrous ether under nitrogen atmosphere at −60° C. The mixture was then allowed to warm to 0° C. and the solution of 2.3 g (10 mmol) of 3,4,5-trimethoxybenzoyl chloride in 20 ml of anhydrous ethyl ether was added in one portion. The resulting mixture was stirred for 10 min. at 0° C. then shaken with 100 ml of 5% aqueous sodium bicarbonate for 5 minutes. The aqueous phase was acidified to pH=˜1 with cold 4N sulfuric acid and extracted with ethyl ether (3×100 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered off and evaporated to dryness to give the title compound as a creamy crystals (1.82 g, 71.6%); 1H NMR (CDCl3) δ 3.8-3.92 (m, 9H, OMe); 4.03 (s, 1.8 H, CH2); 5.62 (s, 0.2 H, CH enol); 7.2 (s, 2H, CH aromatic).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:6]=[CH:7][C:8]1=[N:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]1=2.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30]O.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH:6]=[CH:7][C:8]1=[N:9][CH2:10][CH2:11][N:12]([CH3:20])[C:13]2[CH:18]=[C:17]([O:19][CH2:30][C:26]3[S:25][CH:29]=[CH:28][CH:27]=3)[CH:16]=[CH:15][C:14]1=2
Reactant: OCc1cccs1
Reactant: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccc(OCc3cccs3)cc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 6.8 %

Procedure:
To a stirred solution of 50 mg (0.14 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-8-ol (prepared as described in Example 157) in 5 ml of dry tetrahydrofuran was added 0.014 ml (0.14 mmol) of thiophene-2-methanol and 0.053 ml (0.21 mmol) of tributylphosphine. The solution was cooled, under an atmosphere of nitrogen, to 0° C. and 37 mg (0.21 mmol) of 1,1′-azobis(N,N-dimethylformamide) was added. The mixture was allowed to warm up to room temperature and then stirred for 16 hours. A further 0.053 ml (0.21 mmol) of tributylphosphine and 37 mg (0.21 mmol) of 1,1′-azobis(N,N-dimethylformamide) were added and the mixture stirred for a further 4 hours. The mixture was filtered and the filtrate evaporated and then chromatographed on silica gel using dichloromethane/methanol (98:2) for the elution. There was obtained 4.2 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-8-(2-thenyloxy)-1H-1,4-benzodiazepine as an orange gum MS: m/e 442.8 [M+H]+.
Reaction SMILES: CC1(C)[O:7][C:6](=O)[CH:5]=[C:4]([CH3:9])[O:3]1.[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14]>>[O:3]=[C:4]([CH3:9])[CH2:5][C:6]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[O:7]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: OCC(F)(F)F
Product: CC(=O)CC(=O)OCC(F)(F)F

Procedure:
The title compound is prepared in analogy to example 3 (stage 3a) starting from 2,2,6-trimethyl-1,3-dioxin-4-one and 2,2,2-trifluoroethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH2:17][CH2:18][CH3:19])[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=O)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:17][CH2:18][CH3:19])=[C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[NH:23][N:22]=2)=[CH:4][CH:3]=1
Reactant: CCCC(C(=O)c1ccc(Cl)cc1)C(=O)c1cccs1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCCc1c(-c2ccc(Cl)cc2)n[nH]c1-c1cccs1
Yield: 94.1 %

Procedure:
1-(4-Chlorophenyl)-2-propyl-3-(2-thienyl)-1,3-propanedione (1.4 g, 4.6 mM) was dissolved in ethanol (50 ml), and hydrazine hydrate (343 mg, 6.9 mM) was added thereto. This mixture was heated under reflux for 3 hours. After the mixture was allowed to cool, the solvent was distilled off under reduced pressure. The resulting precipitate was filtered while being washed with a solvent mixture composed of hexane and ether to obtain 1.3 g (4.3 mM) of 3-(4-chlorophenyl)-4-propyl-5-(2-thienyl)-1H-pyrazole, m.p. 129-132° C., in a 94% yield.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]>O1CCOCC1.[OH-].[Na+]>[CH2:1]([S:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:5])=[O:4])[CH3:2]
Reactant: NCCCCCCCC(=O)O
Reactant: CCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)NCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of ethanesulfonyl chloride (1.5 ml, 15.7 mmol) in dioxane (5 ml) was added to a solution of 8-aminooctanoic acid (1 g, 6.28 mmol) in 1N NaOH (22 ml) and dioxane (5 ml), while stirring at 0° C.-5° C. The mixture was allowed to warm to room temperature and stirred for 3.5 minutes. During this period, at 1 hour intervals, the pH was adjusted to 7-8 by addition of 25% NaOH solution. The reaction mixture was washed with diethyl ether (30 ml). The pH was adjusted to 1-2 by addition of 1N HCl and the mixture was extracted with ethyl acetate (70 ml). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with a mixture of diethyl ether. The solid was collected by filtration and dried under vacuum affording 600 mg of the title compound (38% yield).
Reaction SMILES: [CH2:1]=[C:2]([CH:6]([O:11][C:12](=[O:14])[CH3:13])[C:7]([Cl:10])([Cl:9])[Cl:8])[C:3]([O-:5])=[O:4].[CH2:15]=[C:16]([CH:20](O)[C:21](Cl)(Cl)Cl)C([O-])=O.[BH4-].[Na+].CC(=CC(Cl)(Cl)Cl)C(OCCCC)=O>O1CCCC1>[CH3:1][CH:2]([CH:6]([O:11][C:12](=[O:14])[CH3:13])[C:7]([Cl:9])([Cl:10])[Cl:8])[C:3]([O:5][CH2:15][CH2:16][CH2:20][CH3:21])=[O:4]
Reactant: C=C(C(=O)[O-])C(OC(C)=O)C(Cl)(Cl)Cl
Reactant: C=C(C(=O)[O-])C(O)C(Cl)(Cl)Cl
Agent: CCCCOC(=O)C(C)=CC(Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)C(C)C(OC(C)=O)C(Cl)(Cl)Cl
Temperature: 70 °C

Procedure:
1236.1 g of crude 2-methylene-3-acetoxy-4,4,4-trichlorobutyrate (91.3%) containing about 2.5% 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate and 747 ml of tetrahydrofuran was charged to a 2-liter flask equipped with a reflux condenser, magnetic stir bar, and a thermometer. 38.0 g of sodium borohydride was added in three portions to the stirred solution. The reaction temperature rose to 32° C. The reaction was heated slowly to 70° C. for three hours. NMR indicated 80% of the starting material was converted into product, butyl 2-methyl-4,4,4-trichlorobut-2-enoate. The reaction was heated for another six hours at 80° C. and the reaction was quenched by removal of tetrahydrofuran and addition of water. The organic layer was separated and GC analysis showed the presence of 79.2% butyl 2-methyl-4,4,4-trichlorobut-2-enoate, 1% butyl 2-methyl-2,4,4-trichlorobut-3-enoate, 6.6% unreacted starting material, butyl 2-methylene-3-acetoxy-4,4,4-trichlorobutyrate, 3% butyl 2-methyl-3-acetoxy-4,4,4-trichlorobutyrate, and 0.5% butyl 2-methylene-3-hydroxy-4,4,4-trichlorobutyrate. Hydrogenated product, butyl 2-methyl-3-acetoxy-4,4,4-trichlorobutyrate, was formed owing to the presence of water or traces of other protonic solvents in the reaction system.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:28])(=[O:27])[NH2:26])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:36][CH2:37][CH2:38][C:39]#[N:40].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:27])(=[O:28])[N:26]([CH2:12][CH2:11][CH2:10][C:9]#[N:8])[CH2:36][CH2:37][CH2:38][C:39]#[N:40])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(N)(=O)=O)C4(CC4)C3)ncnc21
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)N(CCCC#N)CCCC#N)C4(CC4)C3)ncnc21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-(4-Sulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 2) (112 mg, 0.27 mmol) was dissolved in dry DMF (2 ml), added K2CO3 (38 mg, 0.27 mmol) and cooled to 0° C. A solution of 4-bromobutyronitrile (40 mg, 0.27 mmol) in dry DMF (0.5 mL) was added and the reaction mixture was stirred at rt for 16 h. The crude mixture was treated with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were washed with H2O (2×10 mL), brine (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The products were purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[C:11]([OH:18])[CH:10]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN1CCOCC1.[N:41]([CH2:44][CH2:45][NH2:46])=[N+:42]=[N-:43]>O.CN(C)C=O>[N:41]([CH2:44][CH2:45][NH:46][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:10][C:11]=1[OH:18])=[O:17])=[N+:42]=[N-:43]
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2F)cc1O
Reactant: [N-]=[N+]=NCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCNC(=O)c1ccc(-c2ccc(F)cc2F)cc1O
Temperature: 0 °C
Yield: 60.7 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stir bar was added 2′,4′-difluoro-3-hydroxybiphenyl-4-carboxylic acid (0.301, 1.20 mmol), N,N-Dimethylformamide (5 mL), N,N′-Dicyclohexylcarbodiimide (0.248 g, 1.20 mmol) and n-methylmorpholine (0.25 mL). The reaction mixture was cooled to 0° C. and allowed to stir. Then, 2-azidoethanamine (0.1037 g, 1.20 mmol) was added dropwise and allowed to slowly warm to room temperature while stirring for 24 hr. The reaction mixture was diluted with water, extracted with dichloromethane, washed with 1N HCl, washed with saturated sodium bicarbonate, washed with brine and then concentrated de vacuo. The resulting residue was then purified via silica gel column chromatography (1:40 methanol:dichloromethane to 1:10 methanol:dichloromethane) to give N-(2-azidoethyl)-2′,4′-difluoro-3-hydroxybiphenyl-4-carboxamide (0.232 g, 61% yield). 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), δ 7.47 (d, 1H), δ 7.29 (m, 2H), δ 7.02 (d, 1H), δ 6.88 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 170.3, 160.8, 135.1, 131.3, 131.2, 131.3, 131.2, 126.8, 118.8, 114.6, 112.0, 111.8, 104.8, 104.6, 104.3, 50.7, 39.3 ppm; HRMS (ESI) calcd for C15H12F2N4O3 (M+) 318.0928. found 318.0933.
Reaction SMILES: [NH4+:1].[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:7]([C:10]1[C:11]([O:26][C:27]([CH3:33])([CH3:32])[C:28](OC)=[O:29])=[C:12]([CH2:23][CH2:24][CH3:25])[C:13]2[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[C:14]=2[CH:22]=1)[CH2:8][CH3:9]>C1(C)C=CC=CC=1>[CH2:7]([C:10]1[C:11]([O:26][C:27]([CH3:33])([CH3:32])[C:28]([NH2:1])=[O:29])=[C:12]([CH2:23][CH2:24][CH3:25])[C:13]2[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[C:14]=2[CH:22]=1)[CH2:8][CH3:9]
Reactant: CCCc1cc2c(C(F)(F)F)noc2c(CCC)c1OC(C)(C)C(=O)OC
Reactant: [NH4+]
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCc1cc2c(C(F)(F)F)noc2c(CCC)c1OC(C)(C)C(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of NH4Cl (86 mg) in toluene (10 mL) at room temperature was added AlCl3 (2.0 M, 0.8 mL) dropwise. The reaction was stirred for 3 h. The resultant clear solution was transferred to a solution of methyl 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpropionate (200 mg) in toluene (5 mL). The reaction was stirred at 80° C. overnight, cooled to room temperature, and then partitioned between EtOAc and 1.0 N aqueous HCl solution. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by chromatography gave the desired product. 1H NMR (CDCl3) δ 1.00 (m, 6H), 1.51 (s, 6H), 1.65 (m, 2H), 1.75 (m, 2H), 2.70 (t, 2H), 2.94 (m, 2H), 5.72 (s, broad, 1H), 6.87 (s, broad, 1H), 7.43 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[C:11](=[CH:15]\[N:16](C)C)/[C:12](=[O:14])[CH3:13].NO.Cl>CCO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:15]=[N:16][O:14][C:12]=1[CH3:13]
Reactant: COc1ccc(/C(=C\N(C)C)C(C)=O)c(OC)c1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1ccc(-c2cnoc2C)c(OC)c1

Procedure:
Dissolve (3E)-3-(2,4-dimethoxyphenyl)-4-(dimethylamino)but-3-en-2-one (5.1 g, 20.6 mmol) in EtOH (50 mL) and add NH2OH.HCl (3.05 g, 44.0 mmol). Heat to reflux under N2 for 20 minutes. Cool and evaporate to red-brown oil. Dissolve in CH2Cl2, dry over Na2SO4, filter and concentrate to red-brown oil (4.4 g). Use without further purification. LCMS=220.2 (MH+); 218.2 (M−).