Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:11]([O:15]C)(=[O:14])[CH:12]=[CH2:13].[Li+].[OH-].Cl>C(O)(=O)C.CO>[N:1]1([CH2:13][CH2:12][C:11]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC
Reactant: c1ccc2c(c1)CCCN2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCN1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A mixture of 1,2,3,4-tetrahydroquinoline (3.0 g, 22.5 mmol) and methyl acrylate (3.9 g, 45.0 mmol) in acetic acid (15 mL) was refluxed for 16 hours. Upon cooling, volatiles were removed in the rotary evaporator and the residue obtained was co-evaporated with methanol (3×20 mL) and then dissolved in methanol (15 mL). To this mixture an aqueous solution of LiOH (1.9 g, 45 mmol) was added and it was stirred at room temperature for 2 hours. Reaction mixture was acidified with conc. HCl to pH ˜3 and extracted with ethyl acetate. The organic layer was washed twice with water and brine, dried over MgSO4 and evaporated to dryness to yield 2.91 g of Compound 7 as a dark brown viscous liquid. This product was used without any further purification. The structure of Compound 7 is given below:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](O)=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([N:20]=[N+:21]=[N-:22])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(=O)Oc1ccc(C=CC(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
41.2 g (0.02 mol) of p-acetoxy-cinnamic acid are suspended in 100 ml of benzene and 29 ml (0.4 mol) of thionyl chloride are added. The reaction mixture is heated to the boil under a reflux condenser for half an hour and thereafter the solvent and excess thionyl chloride are removed by distillation in vacuo. The crude p-acetoxy-cinnamic acid chloride which remains is dissolved in 200 ml of absolute dimethoxyethane, 39 g (0.6 mol) of sodium azide are added and thereafter the mixture is stirred for 48 hours at room temperature. The inorganic salts are then filtered off and the filtrate is concentrated in vacuo at 30°C. Hereupon, colourless crystals separate out. The crystallisation is completed by adding ether. p-Acetoxy-cinnamic acid azide of melting point 114°C (decomposition) is obtained.
Reaction SMILES: O=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[C:8]1([S:14]([C:17]#[N:18])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC=CC=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:8]1([S:14]([C:17]2[CH:6]=[C:5]([CH3:7])[CH:4]=[C:2]([CH3:3])[N:18]=2)(=[O:15])=[O:16])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)C=C(C)C
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: Cc1cc(C)nc(S(=O)(=O)c2ccccc2)c1
Temperature: 116 °C
Yield: 49.7 %

Procedure:
First, 9.80 g (100 mmol) of mesityl oxide (4-methyl-3-penten-2-one) and 8.35 g (50.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.15 g (5.00 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 10 hours while agitating at an internal temperature of 116° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 6.14 g of 2-benzenesulfonyl-4,6-dimethylpyridine with the following properties as colorless crystals (purity of 99%, yield of 49% based on benzenesulfonyl cyanide).
Reaction SMILES: Cl.[F:2][C:3]1([C:9]2[S:10][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:12][N:13]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:6]2[CH2:5][CH2:4][C:3]([F:2])([C:9]3[S:10][C:11]([CH2:14][O:15][C:16]4[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=4)=[CH:12][N:13]=3)[CH2:8][CH2:7]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(OCc2cnc(C3(F)CCNCC3)s2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc(N2CCC(F)(c3ncc(COc4ccc(S(C)(=O)=O)cc4)s3)CC2)nc1

Procedure:
A solution of 4-fluoro-4-[5-(4-methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine hydrochloride (1.2 g, 2.76 mmol), 2-chloro-5-ethyl-pyrimidine (425 mg, 1.1 eq.) and DIPEA (1.4 g, 4 eq.) in 2-propanol (20 mL) in a sealed pressure vessel was stirred at 160° C. (oil bath temperature) overnight. After cooling, the solvent was removed in vacuo. The residue was partitioned between water and EtOAc. The organic phase was washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 8.19 (2H, s), 7.90 (2H, d, J=8.8 Hz), 7.73 (1H, d), 7.10 (2H, d, J=8.8 Hz), 5.31 (2H, s), 4.67 (2H, m), 3.44 (2H, m), 3.04 (3H, s), 2.48 (2H, q, J=7.6 Hz), 2.13˜2.38 (4H, m), 1.20 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.[CH3:24][N+:25]([CH3:27])=[CH2:26].[I-]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([CH2:24][N:25]([CH3:27])[CH3:26])=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[C:14]([OH:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: ClCCl
Product: CCCc1cc(CN(C)C)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Reaction time: 0.25 h
Yield: 124.1 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-benzofuran (155 mg gm; 0.5mmole) in methylene chloride (2 mL) was reacted with Eschenmoser's salt (dimethyl methylene-ammonium iodide) (105 mg; 0.5mmole) overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was taken up in ethylacetate, potassium carbonate was added and the mixture was stirred for a period of 15 minutes. The solids were separated and the ethylacetate solution was evaporated to yield 228 mg of 2-(p-methoxybenzyl)--3-methyl-4-hydroxy-5-propyl-7-dimethylaminomethylbenzofuran.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[F:28][C:29]1[CH:48]=[C:47]([N:49]([CH3:73])[CH:50]2[C:54]3[CH:55]=[C:56]4[C:61](=[CH:62][C:53]=3[CH2:52][CH2:51]2)[N:60]=[C:59]([CH3:63])[N:58]([CH2:64][O:65][C:66](=[O:71])[C:67]([CH3:70])([CH3:69])[CH3:68])[C:57]4=[O:72])[CH:46]=[CH:45][C:30]=1[C:31](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:32].ON1C2C=CC=CC=2N=N1>>[F:28][C:29]1[CH:48]=[C:47]([N:49]([CH3:73])[CH:50]2[C:54]3[CH:55]=[C:56]4[C:61](=[CH:62][C:53]=3[CH2:52][CH2:51]2)[N:60]=[C:59]([CH3:63])[N:58]([CH2:64][O:65][C:66](=[O:71])[C:67]([CH3:68])([CH3:69])[CH3:70])[C:57]4=[O:72])[CH:46]=[CH:45][C:30]=1[C:31]([NH:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:32]
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1)CC3
Reactant: N[C@@H](C(=O)O)c1ccc(CC(=O)O)cc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: On1nnc2ccccc21
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(N(C)c1ccc(C(=O)N[C@@H](C(=O)O)c2ccc(CC(=O)O)cc2)c(F)c1)CC3
Yield: 70.6 %

Procedure:
A solution of (R)-α-amino-p-carboxymethylphenylacetic acid (0.1 g, 0.48 mmol) and bis trimethylsilyl acetamide (0.195 g, 0.96 mmol in 5 ml of DMF) was stirred for 20 minutes at room temperature. To the solution was then added pentafluorophenyl o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivalyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzoate (0.213 g, 0.4 mmol), prepared as described in Example 2, followed by N-hydroxybenzotriazole (10 mg) and the stirring was maintained for a further 5 hours. The reaction mixture was then evaporated to dryness and the crude material redissolved in ether. The ether layers were extracted with NaHCO3. The aqueous layers were acidified to pH 2.5 with 2N HCl and the precipiate was filtered off, washed with water and dried under vacuum to give (2R)-2-{o-fluoro-p-[N-methyl-N-((6RS)-2-methyl-4-oxo-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)amino]benzamido}-2-[p-(carboxy-methyl)phenyl]acetic acid (0.19 g), 85%) as a white solid;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Cl)=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9].[CH3:26][NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:27]([C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=3)[CH3:26])=[CH:20][CH:19]=2)=[N:16][CH:15]=[CH:14][N:13]=1)(=[O:10])=[O:9]
Reactant: CNc1ccc(C#N)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1Cl
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2Cl)cc1)c1ccc(C#N)cc1
Yield: 52 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(chloro) benzenesulfonamide (Intermediate 8), and 4-(N-methylamino)-benzonitrile, the title compound was isolated as a yellow solid in 52% yield (99% purity by HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[N:4]=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Nc1c(F)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cccc(Cl)c1N=C=S
Yield: 27.5 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2-chloro-6-fluoro aniline (3.0 g, 19.35 mmol), thiophosgene (5.01 g, 43.47 mmol) and N-ethyl di-isopropyl amine (8.0 g, 64.00 mmol) to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 7.26 (m, 2H), 7.06 (t, J=9.6 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 30 cm3 of dimethyl sulphoxide and 5 g of piperazine is heated at a temperature close to 100° C., with stirring, for 2 hours. The solution obtained at about 100° C. is poured, with stirring, into a mixture of 150 cm3 of water and 50 g of ice. The solution is extracted with 3 times 40 cm3 of trichloromethane. The combined organic phases are extracted with twice 50 cm3 of 0.1 N methanesulphonic acid. 10 g of potassium carbonate are added to the combined aqueous phases. The mixture is extracted with 3 times 40 cm3 of trichloromethane. The combined organic extracts are washed with twice 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue obtained is recrystallized from 25 cm3 of ethanol. 0.8 g of 3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine is obtained in the form of a yellow solid melting at 221° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:23]=[C:6]([C:7]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH:5]=[N:4][CH:3]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1cncc(Br)c1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1cncc(-c2nc3ccccc3n2-c2ccccc2)c1
Temperature: 100 °C
Yield: 88.7 %

Procedure:
Compound 1E (20.0 g, 54.3 mmol) was dissolved in 1,4-dioxane (anhydrous, 150 mL). Phosphorous oxychloride (36 g, 235 mmol) was then added dropwise. The resulting solution was heated at about 100° C. overnight; solids formed. After cooling to RT, the mixture was poured into hexanes (250 mL) to form additional precipitate. Solids were filtered then redissolved in DCM (200 mL) and washed with potassium carbonate (200 mL, saturated solution). The organic phase was collected, dried over sodium sulfate, and loaded onto silica gel. Short silica plug (20% ethyl acetate in hexanes and precipitation from hexanes gave 16.86 g of Compound 1F; 89% yield, pure by HNMR.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([CH3:23])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38]>CO>[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38][CH:17]([C:18]1[S:19][CH:20]=[C:21]([CH3:23])[CH:22]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: Nc1ccccc1S
Reactant: COC(=O)/C(=C/c1cc(C)cs1)NC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1cc(C)cs1

Procedure:
The title compound was prepared according to the method of Example 94b, employing methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-(4-methyl-2-thienyl)acrylate (95b) (3.38 g, 10.2 mmol), triethylamine (0.722 g, 7.14 mmol), and 2-aminothiophenol (6.43 g, 51.4 mmol) in anhydrous methanol (41 mL). The crude product was crystallized from 4:1 (v/v) petroleum ether/ether affording the title compound (2.74 g, 59%) as a pale yellow solid. 1H NMR (300 MHz, d6-DMSO) δ2.04 (s, 3H), 3.38 (s, 3H), 4.56 (t, 1H, J=8.3 Hz), 4.85 (d, 1H, J=7.9 Hz), 5.09 (m, 2H), 5.42 (bs, 2H), 6.36 (t, 1H, J=7.5 Hz), 6.56 (s, 1H), 6.65 (d, 1H, J=7.9 Hz), 6.94-7.02 (m, 3H), 7.30-7.42 (m, 5H), 8.21 (d, 1H, J=9.3 Hz). MS APCI, m/z=457 (M+1). LC/MS: 2.64 min.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[C:9]([CH3:23])[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:23][C:9]1[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=3)[N:3]=[CH:4]2)[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:10]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-n2cnc(I)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.18) (0.33 g, 0.77 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.203 g, 0.92 mmol) according to the general procedure VI. Obtained as an off-white solid (0.100 g, 33%). MS (ISP) 396.1 [(M+H)+]; mp 224-226° C.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1>N.CO>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[CH:26][C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)ccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)ccc32)[C@H](O)[C@@H]1O

Procedure:
A solution of 0.529 g (0.930 mmol) of 84 in 25 mL of NH3 /MeOH was stirred in a pressure bottle at room temperature for 5 h. Volatile materials were removed by evaporation and coevaporation with MeOH (3 x, bath temperature<40° C.). The resulting solid was recrystallized from MeOH/H2O to give 0.316 g (2 crops, 77%) of 85 as white crystals. MP: 167°-169° C. MS: (Cl) m/e 440.8837 (20%, MH+ =440.8852). 1H NMR (DMSO-d6): δ8.05 (d, 1, 7-H, J7-6 =8.5 Hz), 7.59 (d, 1, 6-H), 5.89 (d, 1, 1'-H, J1'-2' =7.5 Hz), 5.51 (d, 1, 2'-OH, J2'-2'OH =6.5 Hz), 5.28 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 5.27 (t, 1, 5'-OH, J5'-5'OH =5.0 Hz), 4.40 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.13 (m, 1, 3'-H, J3'-4' =2.0 Hz), 4.00 (m, 1, 4'-H, J4'-5' =J4'-5' =3.5 Hz), 3.68 (m, 2, 5' -H and 5"-H, J5'-5" =12.0 Hz). 13H NMR (DMSO-d6): δ141.70 (C2), 141.58 (C3a), 132.21 (C7a), 127.42 (C6), 118.06 (C5), 114.08 (C4), 113.87 (C7), 89.45 (C1'), 86.34 (C4'), 71.74 (C2'), 69.62 (C3'), 61.07 (C5'). Anal. Calcd. for C12H11Br2ClN2O4 ; C, 32.57; H, 2.51; N, 6.33. Found: C, 32.70; H, 2.33; N, 6.33.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[C:13](F)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27]CC)=[O:26])=[CH:17][C:16]=2[CH:30]=1>>[Cl:11][C:12]1[C:13]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:14][C:15]2[O:20][CH:19]([C:21]([F:23])([F:22])[F:24])[C:18]([C:25]([OH:27])=[O:26])=[CH:17][C:16]=2[CH:30]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc([N+](=O)[O-])cc3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-nitrophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 246.4-248.3° C. 1H NMR (acetone-d6/300 MHz) 8.34 (d, 2H, J=9.3 Hz), 7.96 (s, 1H), 7.82 (s, 1H), 7.29 (d, 2H, J=9.3 Hz), 7.02 (s, 1H), 5.90 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.3 (d, J=7.2 Hz). ESLRMS m/z 433 (M+NH4). ESHRMS m/z 433.0463 (M+NH4, Calc'd 433.0414). Anal. Calc'd for C17H9ClF3NO6: C, 49.12; H, 2.18; N, 3.37; Cl, 8.53. Found: C, 48.94; H, 2.05; N, 3.32; Cl, 8.72.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>C1COCC1>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: CN1CCC(=O)CC1
Solvent: C1CCOC1
Product: CN1CCC(NC[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
To a solution of (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine (252 mg, 1.26 mmol) and 1-methyl-4-piperidone (0.16 mL, 1.38 mmol) in THF (10 mL) MP-(OAc)3BH resin (Argonaut; 2.33 mmol/g; 1.35 g, 3.15 mmol) was added and the reaction mixture was agitated at room temperature for 24 hours. Then, the reaction mixture was filtered and concentrated in vacuo to afford (R)-3-[(1-methyl-piperidin-4-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (370 mg, 99%) as an orange oil. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].ClC1C(C(OO)=[O:32])=CC=CC=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([S:22]([CH3:23])=[O:32])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=C(OO)c1ccccc1Cl
Reactant: CSc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reaction time: 48 h
Yield: 110 %

Procedure:
A solution of amide from Example 38 (0.2 g) in chloroform (5 ml) was treated with 70% m chloroperbenzoic acid (0.14 g). The reaction mixture was stirred for two days. calcium hydroxide (0.09 g) added and after stirring for a further 0.5 h the mixture was filtered. The filtrate was concentrated under reduced pressure to yield the sub-title product as a white solid (0.23 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18]CC)=O)(=[O:11])=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:34][C:35]1[N:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1>C1COCC1>[Cl:34][C:35]1[N:40]=[C:39](/[CH:41]=[C:16](/[C:15]2[CH:14]=[C:13]([NH:12][S:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])(=[O:11])=[O:10])[CH:23]=[CH:22][CH:21]=2)\[OH:18])[CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: CCOC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a stirring solution of ethyl 3-{[(2,6-difluorophenyl)sulfonyl]amino}benzoate (47.9 g, 140 mmol) in 100 mL anhydrous THF at 0° C. was added 1M LiHMDS in THF (421 mL, 421 mmol). A solution of 2-chloro-4-methylpyrimidine (19.9 g, 154 mmol) in 100 mL of anhydrous THF was added to the reaction mixture over 30 min and warmed to rt. The reaction mixture was quenched with 50 mL of MeOH and concentrated to a black solid under vacuum. The residue was partitioned between DCM and 10% NaHSO4. The aqueous and suspended solids were extracted 2× with DCM and the combined organic extracts were filtered through a pad of Celite, concentrated, and passed through a short silica gel column (elution with THF) to provide 57 g (96%) of the title compound of Step B. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.03-11.34 (m, 1H), 8.49-8.91 (m, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.65-7.76 (m, 2H), 7.55-7.63 (m, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.35-7.47 (m, 1H), 7.22-7.34 (m, 2H), 6.43 (s, 1H), and 4.60 (s, 1H); ES-LCMS m/z 423.93 (M+H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([CH:13]3[NH:17][C:16](=[O:18])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.CI.[C:21]([O-])(O)=O.[Na+]>C1COCC1>[CH3:21][N:17]1[CH:13]([CH:10]2[CH2:9][CH2:8][C:7]3([O:3][CH2:4][CH2:5][O:6]3)[CH2:12][CH2:11]2)[CH2:14][CH2:15][C:16]1=[O:18]
Reactant: O=C([O-])O
Reactant: O=C1CCC(C2CCC3(CC2)OCCO3)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CCC1C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (27 mg, 1.07 mmol, 95%) in THF under argon was added 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidin-2-one (135 mg, 0.60 mmol, prepared in the Example 12 Step E). After stirring 1 hour at room temperature, Methyl iodide (0.07 mL, 1.12 mmol) was added dropwise and the reaction stirred at room temperature overnight. The reaction mixture was poured onto saturated NaHCO3 and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ethyl acetate/DCM).