Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])OC(C)(C)C.Cl.[OH-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([OH:43])[C:33]([N:35]2[C@H:39](C(O)=O)[CH2:38][CH:37]=[N:36]2)=[O:34])=[CH:28][CH:27]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C.CCOC(C)=O.CC(OC)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[N:18]2)=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9]([C@H:39]1[N:35]([C:33](=[O:34])[C@@H:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[OH:43])[N:36]=[CH:37][CH2:38]1)=[O:15]
Reactant: O=C(O)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1-n1cnnn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
In an open vessel, tert-butyl 5-chloro-2-(1H-tetrazol-1-yl)benzylcarbamate (14 g, 45.20 mmol, prepared as described in J. Med. Chem. 2004, 47, 2995, was suspended in acetonitrile (80 mL). HCl (6 M aqueous solution, 37.7 mL, 225.99 mmol) was added and the mixture was then stirred at room temperature for 4 hours. Water (200 mL) and TBME (100 mL) were added. To the aqueous phase and under ice-cooling was added EtOAc (200 mL) followed by slow addition of 2 M NaOH (aq., 130 mL). The organic phase was then washed with water (100 mL). To the EtOAc solution (220 mL) containing the crude (5-chloro-2-(1H-tetrazol-1-yl)phenyl)methanamine was then added (5S)-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxylic acid (7.53 g, 28.28 mmol) followed by the addition of N-methylmorpholine (4.66 mL, 42.43 mmol). To this clear homogenous solution was then added TBTU (10.90 g, 33.94 mmol) in one portion. The mixture was then stirred at room temperature over night. The precipitate formed was filtrated and then washed with TBME (100 mL). After drying in vacuo, the desired compound was obtained as a solid (7.65 g, 59%). The mother liquor was diluted with EtOAc and washed with Na2CO3 (aq., sat), water and 1 M HCl (aq.). Crystallization from CH3CN/water gave 4.59 g of the title compound. Total yield 88%. 1H NMR (600 MHz, CD3CN) δ 2.93 (ddd, 1H), 3.10 (ddd, 1H), 4.15-4.19 (m, 2H), 4.25 (dd, 1H), 4.60 (dd, 1H), 5.73-5.76 (m, 1H), 6.97-6.99 (m, 1H), 7.07-7.10 (m, 2H), 7.28-7.30 (m, 1H), 7.42-7.46 (m, 3H), 7.54-7.56 (m, 1H), 7.71 (d, 1H), 9.20 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Cl.[F:12][CH2:13][CH2:14][NH2:15].C(N(C(C)C)CC)(C)C>C(O)C>[F:12][CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCF
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(NCCF)nc1
Yield: 45 %

Procedure:
A stirred mixture of 2-chloro-5-nitropyridine (2.4 g, 0.015 mol), 2-fluoroethylamine hydrochloride (1.75 g, 0.0175 mol) and diisopropylethylamine (7.0 ml, 0.040 mol) in absolute ethanol (50 ml) was kept under nitrogen at ambient temperature (24° C.) for 22 hours, warmed slowly to the reflux temperature during 6 hours and refluxed for 18 hours. It was then concentrated in vacuo. The residue was mixed with saturated NaHCO3 and extracted with EtOAc. The extract was washed with water and brine, dried (MgSO4) and concentrated. The residue was chromatographed on silica gel with CH2 cl2. The product was crystallized from methyl tert butyl ether to give 1.25 g of the titled product, mp 126°-127° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:30]=[CH:29][C:12]2[NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[N:15][C:11]=2[CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:30]=[CH:29][C:12]2[NH:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:15][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3cc(Cl)ccc3[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2[nH]c(N3CCNCC3)nc2c1
Reaction time: 1 h

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 4-(5-chloro-1H-benzimidazol-2-yl)piperazine-1-carboxylate (72 mg) in DCM (2 mL) and the reaction was stirred for 1 h. The solvent was then evaporated under high vacuum for 1 h to afford the title compound as a gum which was used without further analysis.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]1=[O:15].[O:16]=[C:17]1[N:21]([C:22]2[CH:23]=[CH:24][C:25]3[S:26][CH2:27][C:28](=[O:32])[NH:29][C:30]=3[N:31]=2)[CH2:20][C@@H:19]([CH2:33]OS(C)(=O)=O)[O:18]1>>[O:16]=[C:17]1[N:21]([C:22]2[CH:23]=[CH:24][C:25]3[S:26][CH2:27][C:28](=[O:32])[NH:29][C:30]=3[N:31]=2)[CH2:20][C@@H:19]([CH2:33][NH:1][CH2:2][CH2:3][N:4]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]2=[O:15])[O:18]1
Reactant: NCCn1c(=O)[nH]c2ccccc2c1=O
Reactant: CS(=O)(=O)OC[C@@H]1CN(c2ccc3c(n2)NC(=O)CS3)C(=O)O1
Product: O=C1CSc2ccc(N3C[C@@H](CNCCn4c(=O)[nH]c5ccccc5c4=O)OC3=O)nc2N1
Yield: 18 %

Procedure:
Starting from 3-(2-aminoethyl)-2,4(1H,3H)-quinazolinedione (prepared according to J. Med. Chem. (1992), 35(26), 4903-10) and methanesulfonic acid (S)-2-oxo-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)-oxazolidin-5-ylmethyl ester (prepared in analogy to its (R)-enantiomer, described in WO 2010/041194) and using Procedure F, the title compound was obtained as a yellow solid (21 mg; 18% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]2O)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:20])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]2[Cl:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(Cl)Cl
Reactant: CC1=C(C)C(O)N(c2ccc(Cl)c(Cl)c2)C1=O
Product: CC1=C(C)C(Cl)N(c2ccc(Cl)c(Cl)c2)C1=O
Reaction time: 1 h

Procedure:
27.2 g of N-(3',4'-dichlorophenyl)-3,4-dimethyl-2-hydroxy-5-oxo-2,5-dihydropyrrole (see Example 3) is added to 25 ml of thionyl chloride, with an intense evolution of gas occurring. After being stirred for one hour at 50°, the mixture is concentrated by evaporation in vacuo. The solid residue is triturated with petroleum ether to obtain 27.4 g (95% of theory) of the above compound in the form of light-yellow crystals, m.p. 95°-96°.
Reaction SMILES: C(N(CC)[C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)=[O:5])C>C1COCC1>[S:8]1[CH:9]=[CH:10][C:6]2[C:4](=[O:5])[C:7]3[S:8][CH:9]=[CH:10][C:6]=3[C:4](=[O:5])[C:7]1=2
Reactant: CCN(CC)C(=O)c1ccsc1
Solvent: C1CCOC1
Product: O=C1c2ccsc2C(=O)c2ccsc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-diethylthiophene-3-carboxamide (18.3 g, 0.1 mol) was dissolved in THF (100 mL) in a flame dried flask kept under an inert atmosphere. The reaction flak was placed in an ice bath followed by the dropwise addition of n-BuLi (40.0 mL, 2.5 M BuLi in hexane) over a period of 30 minutes. The reaction mixture was then allowed to warm to room temperature and stirred over a period of 2 hours. The reaction mixture was subsequently slowly poured into ice water (250 mL) and stirred for several hours. The resulting reaction mixture was filtered and the yellow precipitate washed successively with water, methanol (50 mL) and hexanes (50 mL). The title compound was obtained as a yellow powder (yield: 75%): GC-Ms: 220; 1H NMR (400 MHz, CDCl3,ppm) δ: 7.69-7.68(d, 2H), 7.65-7.64(d, 2H); 1H NMR (400 MHz, DMSO-d6, ppm) δ: 8.12-8.11(d, 2H), 7.60-7.59(d, 2H); 13C NMR (100 MHz, CDCl3, ppm) δ: 174.7, 145.1, 143.1, 133.8, 126.8.
Reaction SMILES: [N+:1]([C:4]1C(C#N)=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[Sn](Cl)Cl.Cl.[C:22]([O:25]CC)(=[O:24])[CH3:23]>CN(C=O)C.C(N(CC)CC)C>[NH2:1][C:4]1[C:23]([C:22]([OH:25])=[O:24])=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1
Reactant: N#Cc1ncc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1cc(-c2ccccc2)cnc1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-5-phenylpicolinonitrile (1 eq) in 10 mL of DMF was added tin (II) chloride dehydrate (7.0 eq) at room temperature. The reaction mixture was stirred at that temperature overnight. The mixture was diluted with 150 mL of ethyl acetate and 30 mL of triethyl amine. After filtration, the filtrate was concentrated under reduced pressure to give a solid, which was added 2 mL of concentrated HCl. The mixture was stirred in microwave at 90° C. for 10 minutes. After standing over night, the solid was collected by filtration, which was dissolved in 10 mL of 1N NaOH. The resulting mixture was extracted with 50 mL of ethyl acetate. The aqueous layer was acidified by 1 N HCl to pH 7.0 to yield 3-amino-5-phenylpicolinic acid, which was collected by filtration. LC/MS (m/z): 215.1 (MH+).
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:16][C:17]([F:22])([F:21])[C:18](O)=O.Cl>>[N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]3[NH:14][C:18]([C:17]([F:22])([F:21])[F:16])=[N:15][C:10]=3[CH:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(c1ccc(N)c(N)c1)n1ccnc1
Agent: Cl
Product: CC(c1ccc2[nH]c(C(F)(F)F)nc2c1)n1ccnc1
Reaction time: 6 h
Yield: 69.3 %

Procedure:
A mixture of 3.6 parts of 4-[1-(1H-imidazol-1-yl)ethyl]-1,2-benzenediamine, 5 parts of trifluoroacetic acid and 100 parts of a hydrochloric acid solution 4N was stirred for 6 hours at reflux temperature. The reaction mixture was concentrated and the concentrate was dissolved in 50 parts of water. The mixture was made alkaline with sodium hydrogen carbonate and the product was extracted with dichloromethane. The extract was dried, filtered and concentrated. The concentrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was concentrated. The concentrate was crystallized from 20 parts of ethyl acetate. The product was filtered off and dried, yielding 3.4 parts (69.3%) of 5-[1-(1H-imidazol-1-yl)ethyl]-2-(trifluoromethyl)-1-H-benzimidazole; mp. 164.6° C. (compound 64).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1.C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[N:11][N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)Cc1cnc(-n2cnnn2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: O=C(O)Cc1cnc(-n2cnnn2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To tert-butyl 2-(5-fluoro-6-(1H-tetrazol-1-yl)pyridin-3-yl)acetate (70 mg, 0.25 mmol) in DCM (0.50 mL) was added thioanisole (163 μl, 1.38 mmol) and TFA (241 μl, 3.13 mmol) at 0° C. The reaction mixture was stirred at rt for 5 h. The reaction mixture was concentrated to give the crude product, which was used in the next step without further purification: LC/MS: [(M+1-28)]+=196.5.
Reaction SMILES: CC(C)(C)[C@H](NC(=O)[C@@H](NC)C)C(N1[C@H](C(N[C@H]2C3C(=CC=CC=3)CCC2)=O)CC2C(=CC(N[C@H]3C[C@@H](C(=O)N[C@H]4C5C(=CC=CC=5)CCC4)N(C(=O)[C@@H](NC(=O)[C@@H](NC)C)C(C)(C)C)C3)=CC=2)C1)=O.[C:71]([O:75][C:76]([N:78]1[C@H:82]([C:83]([O:85][CH3:86])=[O:84])[CH:81]=[C:80]([C:87]2[CH:96]=[C:95]3[C:90]([CH2:91][C@@H:92]([C:104]([O:106][CH3:107])=[O:105])[N:93]([C:97]([O:99][C:100]([CH3:103])([CH3:102])[CH3:101])=[O:98])[CH2:94]3)=[CH:89][CH:88]=2)[CH2:79]1)=[O:77])([CH3:74])([CH3:73])[CH3:72]>>[C:71]([O:75][C:76]([N:78]1[C@H:82]([C:83]([O:85][CH3:86])=[O:84])[CH2:81][C@H:80]([C:87]2[CH:96]=[C:95]3[C:90]([CH2:91][C@@H:92]([C:104]([O:106][CH3:107])=[O:105])[N:93]([C:97]([O:99][C:100]([CH3:102])([CH3:101])[CH3:103])=[O:98])[CH2:94]3)=[CH:89][CH:88]=2)[CH2:79]1)=[O:77])([CH3:74])([CH3:72])[CH3:73]
Reactant: COC(=O)[C@@H]1C=C(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)[C@H](C(=O)OC)C3)CN1C(=O)OC(C)(C)C
Agent: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc(N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C
Product: COC(=O)[C@@H]1Cc2ccc([C@H]3C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C3)cc2CN1C(=O)OC(C)(C)C
Yield: 88.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Compound C of Example 20, (S)-2-tert-butyl 3-methyl 7-((5)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)-2,5-dihydro-1H-pyrrol-3-yl)-3,4-dihydroisoquinoline-2,3(1H)-dicarboxylate (563 mg, 1.09 mmol) was converted to the title compound (500 mg, 88%). MS (ESI) m/z 519.5 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.[CH2:18](I)[CH3:19]>>[N+:14]([C:10]1[CH:9]=[C:8]([CH:7]([CH2:18][CH3:19])[C:6]([OH:5])=[O:17])[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Product: CCC(C(=O)O)c1cccc([N+](=O)[O-])c1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using ethyl iodide (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 2-(3-nitrophenyl)butyric acid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[C:24]([O:23][C:19]([NH:20][NH:21][C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=2)[CH2:9]1)=[O:16])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
A mixture of 1-(4-fluoro-benzoyl)-(S)-piperidine-3-carboxylic acid (1.05 g, 4.17 mmol), tert-butyl carbazate (0.55 g, 4.17 mmol), HOBT (0.562 g, 4.17 mmol), EDCI.HCl (1.2 g, 6.25 mmol) in dry dichloromethane (8 mL) was kept under stirring overnight at ambient temperature, under nitrogen atmosphere. HCl 1N (30 mL) was then added and the phases separated. The organic layer was washed with HCl 1N (30 mL), with NaOH 1N (30 mL×2 times), then with water (30 mL). Evaporation of the organic solvent afforded a crude yellow oil which was purified by flash chromatography (silica gel, eluent: DCM/MeOH 70/1) to give 0.715 g of N′-[1-(4-fluoro-benzoyl)-(S)-piperidine-3-carbonyl]-hydrazinecarboxylic acid-tert-butyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[Cl:27][C:28]1[C:29](I)=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:26][C:8]1[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[C:28]([Cl:27])=[CH:37][CH:36]=[CH:35][C:30]=3[C:31]([O:33][CH3:34])=[O:32])[CH:14]=2)[N:9]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: COC(=O)c1cccc(Cl)c1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Product: COC(=O)c1cccc(Cl)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 60 °C

Procedure:
A vial was charged with 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (1.07 g, 3 mmol, prepared as in Example 2, Step 1-2), methyl 3-chloro-2-iodobenzoate (889 mg, 3.00 mmol), Pd(OAc)2 (33.7 mg, 0.150 mmol), triphenylphosphine (79 mg, 0.300 mmol) and potassium phosphate (0.497 mL, 6.00 mmol). The vial was evacuated and backfilled with nitrogen gas 3×. Acetonitrile (8 mL) and Water (2 mL) were added and the reaction mixture was heated to 60° C. overnight in an oil bath. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (5% MeOH in DCM). Methyl 2-(2-amino-3-morpholinoquinolin-6-yl)-3-chlorobenzoate was obtained as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[K].[S:15]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1)(=[O:18])(=[O:17])[NH2:16]>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:16][S:15]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH:7]=1
Reactant: Clc1cc(Cl)nc(N2CCCC2)n1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCCC3)n2)cc1
Yield: 58.9 %

Procedure:
0.58 g (0.00266 mol) of 4,6-dichloro-2-pyrrolidin-1-yl-pyrimidine and 1.36 g (0.00539 mol) of N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was made acid with 4N HCl and extracted with ethyl acetate. Both organic phases were combined and concentrated. The residue was recrystallized from a small amount of ethanol and the mother liquor was chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. There was obtained a total of 0.62 g (66%) of N-[4-(6-chloro-2-pyrrolidin-1-yl-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as whitish crystals; m.p. 229-233° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[O:16])[NH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17]([O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=1)[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:17]([O:19][C:20](=[O:31])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:11]2=[O:16])=[CH:27][CH:28]=1)[CH3:18]
Reactant: O=c1[nH]cccc1-c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1

Procedure:
3-(4-Nitrophenyl)-1H-pyridin-2-one (P3, 200 mg, 0.93 mmol), 3-(4-chloromethyl-phenyl)propionic acid ethyl ester (P6, 270 mg, 1.20 mmol) and cesium carbonate (900 mg, 2.78 mmol) were stirred for 18 hours in dimethyl formamide (5 mL) at room temperature. The reaction mixture was filtered through celite (Diatomaceous Earth), concentrated and the crude mixture was purified by chromatography on silica gel (50% v/v ethyl acetate in petroleum ether) to afford the title compound as a solid.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:7]=[C:8]([C:12]2([NH2:22])[CH2:21][CH2:20][C:15]3(OCC[O:16]3)[CH2:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+]>C(O)(=O)C.O>[NH2:22][C:12]1([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=2)[CH2:13][CH2:14][C:15](=[O:16])[CH2:20][CH2:21]1
Reactant: CC(C)(C)c1cccc(C2(N)CCC3(CC2)OCCO3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cccc(C2(N)CCC(=O)CC2)c1

Procedure:
A solution of 8-(3-tert-Butyl-phenyl)-1,4-dioxa-spiro[4.5]dec-8-ylamine hydrochloride (337 mg, 1.03 mmol) in glacial acetic acid (9 mL) and water (4 mL) was heated to 75° C. for 21 h, whereupon the reaction was deemed complete by HPLC analysis. The reaction mixture was basified with 2.5 N NaOH solution, then extracted with ethyl acetate (3×25 mL). The combined organic layers were washed (brine), dried (Na2SO4), filtered and concentrated under reduced pressure. Material was pure by HPLC/MS: retention time=1.18 min, method [7]; mass spec (ESI) 246 (MH+, 33), 229 (M−NH2+, 100), 228 (28), 173 (47).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O:23]C)=[O:22])[CH:14]=[CH:13]1)[CH2:2]2.O.O.[OH-].[Li+:28]>C1COCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([NH:9][CH2:10][CH2:11][N:12]1[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[C:21]([O-:23])=[O:22])[CH:14]=[CH:13]1)[CH2:2]2.[Li+:28]
Reactant: COC(=O)c1cccc2ccn(CCN[C@@H]3CN4CCC3CC4)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cccc2ccn(CCN[C@@H]3CN4CCC3CC4)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (S)-methyl 1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate (1.4 g, 4.3 mmol) from Step C above in THF (20 ml) and water (20 ml) was added lithium hydroxide monohydrate (535 mg, 12.8 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was dried overnight under vacuum to afford crude lithium (S)-1-(2-(quinuclidin-3-ylamino)ethyl)-1H-indole-7-carboxylate which was used in the next step without further purification: MS (ESI+) m/z 314 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([N:18]=O)=[C:13]([NH2:20])[N:12]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:12]=[C:13]([NH2:20])[C:14]([NH2:18])=[C:15]([NH2:17])[N:16]=1
Reactant: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N=O
Agent: O=S(=O)(O)O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(SCc2cccc(F)c2F)nc(N)c1N
Temperature: 0 °C

Procedure:
To a suspension of the product of step (b) (2 g) in boiling water (40 ml) was added Na2S2O4 (5.4 g) portion-wise. The suspension was allowed to cool and then 50% sulphuric acid was added slowly and then the mixture was cooled to 0° C. The solid was isolated by filtration and washed with cold water, then dried over P2O5 at 50° C. to give the sub-titled product as a yellow solid.