Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:21]([F:24])([F:23])[F:22])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[C:17]#[C:18][CH2:19][CH3:20])=[O:5])C.C1COCC1.CCO.O.O[Li].O.Cl>O>[C:17]([C:10]1[CH:11]=[C:12]([Cl:16])[CH:13]=[C:14]2[C:9]=1[O:8][CH:7]([C:21]([F:22])([F:23])[F:24])[C:6]([C:4]([OH:5])=[O:3])=[CH:15]2)#[C:18][CH2:19][CH3:20]
Reactant: CCC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCC#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To 0.768 g (2.14 mmole) of ethyl-8-but-1-ynyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3- carboxylate was added 11 mL of a solvent mixture of THF/EtOH/H2O (7:2: 1) followed by 135 mg (3.22 mmole) of LiOH—H2O. The mixture was stirred at 60° C. for two hours. The mixture was concd, treated with water, and acidified with 0.5N HCl. The crude solid was purified by reverse phase chromatography to afford 0.575 g (81%) of a yellow crystalline solid: 1H NMR (CDCl3/400 MHz) 1.24 (t, 3H, J=7.2 Hz), 2.46 (q, 2H, J=7.6 Hz), 5.74 (q, 1H J=6.8 Hz), 7.16 (d, 1H, J=2.8 Hz), 7.39 (d, 1H, J=2.4 Hz), 7.81 (s, 1H); MS (ES+) 331 (M+1, 100); HRMS (ES−) m/z calcd for (C15H10O3ClF3) 329.0187, found 329.0202.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([CH3:13])[CH2:11][C:10]([NH:14][CH:15]=[O:16])=[N:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([CH3:13])[CH2:11][C:10]([NH:14][C:15](=[O:16])[CH3:17])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC1CC(NC=O)=NN1c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)NC1=NN(c2ccc(Cl)cc2)C(C)C1
Reaction time: 48 h

Procedure:
A mixture of 8.0 g. of 3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline (prepared as described in Example 20), 400 mg. of 4-dimethylaminopyridine and 20.0 ml. of acetic anhydride is allowed to stand at room temperature for 48 hours. The solid formed is collected by filtration, washed with cold acetic anhydride, then with hexane and is dried to give a white solid. The solid is recrystallized from dichloromethane-hexane to give 6.6 g. of the product of the Example as a white solid, m.p. 167°-169° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])=O.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[OH:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2.N1CCCCC1>C(O)C>[NH2:14][C:13]1[O:16][CH:17]2[C:18]3[C:22](=[CH:23][CH:24]=[C:25]2[CH:1]([C:3]2[CH:4]=[N:5][CH:6]=[C:7]([C:8]#[N:9])[CH:10]=2)[C:12]=1[C:11]#[N:15])[N:21]=[CH:20][CH:19]=3
Reactant: N#Cc1cncc(C=O)c1
Reactant: N#CCC#N
Reactant: Oc1cccc2[nH]ccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC1=C(N)OC2C3=CC=NC3=CC=C2C1c1cncc(C#N)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 797.9 %

Procedure:
To a clear solution of 5-formyl-nicotinonitrile (0.0063 g, 0.048 mmol), ethanol (0.24 mL) and malononitrile (0.0031 g, 0.0048 mmol) was added 4-hydroxyindole (0.0064 g, 0.048 mmol) and piperidine (2.4 μL, 0.024 mmol). The resultant dark green solution was stirred at room temperature for 6 h, concentrated to a gray solid and extracted with EtOAc (30 mL). The organic layer was washed with water (5 mL), dried over MgSO4, filtered through sintered glass and concentrated to yield 0.012 g (80%) of a green solid. Purification by column chromatography (elution with EtOAC:hexanes, 1:2) yielded 0.006 g (40%) of the above compound as a white solid. 1H-NMR (Acetone-d6): 10.54 (s, 1H), 8.83 (t, J=2.20, 1.65 Hz, 2H), 8.09 (t, J=2.20, 1.92 Hz, 1H), 7.39 (t, J=2.75 Hz, 1H), 7.20 (dd, J=8.24, 0.82 Hz, 1H), 6.77 (dd, J=8.24 Hz, 1H), 6.58 (m, J=2.20, 1.92, 0.82 Hz, 1H), 6.42 (s, 2H), 5.09 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].COC1C=C(C(O)[C:25]([O:27][CH3:28])=[O:26])C=CC=1OC>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]([OH:5])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C(O)c1ccc(OC)c(OC)c1
Reactant: COc1cc(F)c(C=O)cc1OC
Product: COC(=O)C(O)c1cc(OC)c(OC)cc1F
Yield: 44 %

Procedure:
7A (1.05 g, 44%) was prepared in 2 steps from 2-fluoro-4,5-dimethoxybenzaldehyde following procedures analogous to the preparation of 6B. LC-MS: 267.11 (M+Na)+.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][C:6]([CH:7]=[N:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[Br:25][CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[Br-:25].[CH3:24][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[N:8][N+:9]2[CH:13]=[CH:12][N:11]([CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:10]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(-c2nccn2N=Cc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CC#N
Product: COc1ccc(-c2n(CC(=O)C(C)(C)C)cc[n+]2N=Cc2ccc(N(C)C)cc2)cc1
Product: [Br-]

Procedure:
A solution of 160 mg of 1-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)imidazole and 400 mg of 1-bromo-3,3-dimethyl-2-butanone in 3 ml of acetonitrile is stirred at 60° for 20 hours. The product is removed by filtration and washed with ether. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-(p-methoxyphenyl)-3-(pivaloylmethyl)imidazolium bromide of melting point 262°.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:10])=[O:4].C([Li])CCC.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C#N)=[CH:19][CH:18]=1>O1CCCC1>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[CH:9]=[CH:8][S:7][C:6]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CNC(=O)c1ccsc1C
Reactant: N#Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2sccc12
Temperature: -70 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
To a solution of N-methyl-2-methylthiophene-3-carboxamide (13.0 g) in tetrahydrofuran (130 ml) was dropwise added 2.5 M butyl lithium (74 ml) at −70° C. The reaction solution was stirred at −70° C. for 2 hr, followed by the addition of 4-bromobenzonitrile (15.3 g) at once. After the dry ice/acetone bath was removed, the reaction mixture was back to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride and ether were added thereto, and then the resulting mixture was further stirred for 1 hr. The resulting white precipitates were collected by filtration, and washed with water, ether and n-hexane in this order. The resulting product was dried to give the title compound (4.9 g, yield; 19%).
Reaction SMILES: [CH2:1]([N:4]1[CH2:14][CH:13]2[O:15][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:16])=[CH:9][CH:8]=3)[CH2:5]1)[C:2]#[CH:3].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:35])=[CH:20][N:19]=1.Cl>C(O)(C)C.C([O-])(O)=O.[Na+]>[Cl:35][C:21]1[C:22]([NH:24][C:25]2[CH:34]=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[O:15][CH:13]3[CH2:14][N:4]([CH2:1][C:2]#[CH:3])[CH2:5]2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: C#CCN1CC2OC(C1)c1cc(N)ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: C#CCN1CC2OC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Temperature: 140 °C
Yield: 50.4 %

Procedure:
10-Prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (71 mg, 0.33 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (99 mg, 0.33 mmol) were combined with 4 N HCl (0.083 mL, 0.33 mmol) in isopropanol (2 mL) and heated in a microwave at 140° C. for 10 min. The resulting mixture was diluted with saturated aqueous NaHCO3 (5 mL), extracted with CH2Cl2 (2×5 mL), dried over MgSO4, filtered, and concentrated. The remaining residue was purified with silica gel chromatography (30-100% EtOAc in hexanes) to obtain 2-[5-Chloro-2-(10-prop-2-ynyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a light yellow solid (79 mg, 50%). 1HNMR (400 MHz, CDCl3) δ 11.0 (bs, 1H), 8.6 (d, 1H, J=8.7 Hz), 8.1 (s, 1H), 7.6 (s, 1H), 7.5 (d, 1H, J=7.8 Hz), 7.4 (appt t, 1H, J=8.7 Hz), 7.3 (d, 1H, J=7.8 Hz), 7.2 (d, 1H, J=7.8 Hz), 7.1 (appt t, 1H, J=7.6 Hz), 7.0 (bs, 1H), 6.2 (bs, 1H), 5.1 (s, 1H), 5.0 (s, 1H), 3.2 (d, 2H, J=2.4 Hz), 3.1-3.0 (m, 5H), 2.6 (t, 2H, J=9.5 Hz), 2.2 (t, 1H, J=2.4 Hz); MS (m/e) 475 (M+1); mp 117-121° C.
Reaction SMILES: Cl[C:2]1([C:12]2[S:13][C:14]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[CH:15][N:16]=2)[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1>CO.[Pd]>[O:9]1[C:5]2([CH2:10][CH2:11][CH:2]([C:12]3[S:13][C:14]([C:17]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[O:18])=[CH:15][N:16]=3)[CH2:3][CH2:4]2)[O:6][CH2:7][CH2:8]1
Reactant: O=C(c1cnc(C2(Cl)CCC3(CC2)OCCO3)s1)N1CCCC1
Agent: [Pd]
Solvent: CO
Product: O=C(c1cnc(C2CCC3(CC2)OCCO3)s1)N1CCCC1
Yield: 96.8 %

Procedure:
To a Parr hydrogenation bottle was added 2-(8-chloro-1,4-dioxaspiro[4.5]dec-8-yl)-5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole (0.095 g, 0.266 mmol), dissolved in methanol (10 mL), followed by the addition of 10% Pd/C (0.02 g). This mixture was hydrogenated at 50 psi overnight. After the catalyst was filtered and washed with methanol, the filtrate was concentrated in vacuo to give 0.083 g of 2-(1,4-dioxaspiro[4.5]dec-8-yl)-5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazole in 97% yield. MS (EI) calcd: (M+H)+=322.1. Found: 322.0.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.CC([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[CH:31][CH:30]=1)C(=O)[O-])(C)C>>[NH2:24][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[CH2:39][CH2:38][N:37]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:36]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)N(Cc1ccc(C2CCNC2)cc1)C(=O)[O-]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: NCc1ccc(C2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)cc1

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.88 g, 3.3 mmol) and 1,1-dimethylethyl[[4-(3 pyrrolidinyl)-phenyl]methyl]carbamate, a procedure analogous to that given in Example 6 provided the title compound (1.02 g) as a bright yellow solid, mp 268°-272° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[S:8][CH:6]1[OH:7])(=[O:3])[CH3:2].O.[C:26]1(C)C=[CH:30][C:29](S(O)(=O)=O)=[CH:28][CH:27]=1.C(=O)(O)[O-:38].[Na+]>C(Cl)(Cl)Cl.O1C=CCCC1>[O:38]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[C:6]1([S:8][C@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2])[OH:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C1=COCCC1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)OC[C@H]1SC(O)(C2CCCCO2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.0 g, 5.49 mmoL) in chloroform (40 mL), 3,4-dihydro-2H-pyran (1.5 mL, 16.5 mmoL) and p-toluenesulfonic acid monohydrate (104 mg, 0.549 mmoL) were added and stirred at room temperature for 1 hour. After addition of saturated aqueous sodium bicarbonate, the reaction mixture was extracted with chloroform, and the organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the titled compound (2.56 g) as a light-yellow amorphous substance.
Reaction SMILES: [SiH4].[CH2:2]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12])[CH2:3][CH2:4][CH3:5].C(OCC)(=[O:15])C.[C:19]1([CH3:25])C=CC=C[CH:20]=1>>[CH2:25]([O:12][CH:11]([OH:15])[CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH:19]=[CH2:20]
Reactant: CCOC(C)=O
Reactant: CCCCOCCOCCO
Reactant: Cc1ccccc1
Agent: [SiH4]
Product: C=CCOC(O)COCCOCCCC
Yield: 60 %

Procedure:
All procedures were the same as for preparation of compound 1 except that diethylene glycol monobutyl ether (45.3 mL, 260 mmoles) was used. After filtering the sodium bromide precipitate and concentrating the filtrate, the product was chromatographed on silica gel (eluents: toluene, 2.5% ethyl acetate in toluene, then 5% ethyl acetate in toluene), to produce a 60% yield of colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Cl:25])C(=O)C1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[Cl:25]
Reactant: CCn1nccc1-c1cc(C(=O)OC)sc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1cc(C(=O)OC)sc1Cl
Yield: 73.9 %

Procedure:
Methyl 5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.8 g, 6.65 mmol) and NCS (1.3 g, 9.74 mmol) in THF (10 mL) were heated to 70° C. under N2 for 2 h. The reaction solution was concentrated and purified on silica (EtOAc/Hex, 10-30%) to afford the title compound (1.5 g, 74%) as a syrup: LC-MS (ES) m/z 305 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3](OCCCl)=[O:4].[C:16]([O:20][CH:21]([CH3:23])[CH3:22])(=[O:19])[CH2:17][OH:18].C(C1C=CC=CC=1)(C)(C)C>C(OCC)C>[OH:1][CH:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:18][CH2:17][C:16]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: CC(C)OC(=O)CO
Reactant: O=C(OCCCl)C(O)Cc1ccccc1
Solvent: CCOCC
Solvent: CC(C)(C)c1ccccc1
Product: CC(C)OC(=O)COC(=O)C(O)Cc1ccccc1

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25 M 2-chloroethyl 2-hydroxy-3-phenylpropionate, 0.25 M isopropyl glycolate, and 1.0% tert-butylbenzene was added to 0.43 g Lipase AK. After mixing for 2 d at room temperature, the conversion of 2-chloroethyl 2-hydroxy-3-phenylpropionate to the title compound was estimated (by GC, Method B) to be approximately 28%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C13H14O5Tms (M--CH3) 323.1314, obsd 323.1290. In identical reactions substituting Lipase P30, Lipase G, Lipase MAP10, porcine pancreatic lipase, Lipase AP12 or Protease M for Lipase AK, the relative values for conversions at 2 d (Lipase AK=100) were 88, 85, 76, 51, 7, and 7%, respectively.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:11]([OH:24])[CH:10]([CH:25]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](Cl)=[O:47])=[CH:44][CH:43]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH:11]([OH:24])[CH:10]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4].[Cl:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([O-:5])=[O:47])=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCCN(C(=O)OC(C)(C)C)CC(C2CCCCCCCC2)C(O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([O-])c1ccc(Cl)cc1
Reaction time: 2.5 h

Procedure:
To 3,7-di(tert-butoxycarbonyl)-3,7-diazabicyclononan-9-ol (475 mg, 1.39 mmol) in methylene chloride (25 mL) was added triethylamine (0.390 mL), 4-chlorobenzoyl chloride (0.23 mL, 1.81 mmol), and 4-dimethylaminopyridine (221 mg, 1.81 mmol). The reaction mixture was stirred for 2.5 h and was then diluted with methylene chloride and washed with 0.5N aqueous HCl and water. After drying over sodium sulfate the solution was concentrated and the residue was purified by column chromatography on silica gel with 25% ethyl acetate in hexanes to give the title compound (611 mg, 91%). 1H NMR (300 MHz, CDCl3) 1.18 (s, 18H), 1.80 (s, 3H), 3.00 (t, 2H), 3.31 (t, 2H), 3.99 (m, 3H), 4.30 (m, 2H); mass spectrum m/z 365 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][CH:15]2[CH2:18][N:17]([C:19]([O:21]C(C)(C)C)=O)[CH2:16]2)=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:33](N(CC)C(C)C)(C)[CH3:34].[C:42](Cl)(=[O:45])[CH2:43][CH3:44]>O.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]([CH2:14][CH:15]3[CH2:16][N:17]([C:19](=[O:21])[CH2:33][CH3:34])[CH2:18]3)=[N:12][N:11]([C:42](=[O:45])[CH2:43][CH3:44])[C:9]2=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC(=O)NNC(=O)Nc2ccc(Br)cc2)C1
Reactant: CCC(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)N1CC(Cc2nn(C(=O)CC)c(=O)n2-c2ccc(Br)cc2)C1
Temperature: 130 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
In a round bottom flask equipped with reflux condenser, a mixture of 1,1-dimethylethyl 3-[2-(2-{[(4-bromophenyl)amino]carbonyl}hydrazino)-2-oxoethyl]-1-azetidinecarboxylate (5.69 mmol) and potassium carbonate (28.5 mmol) in water (110 mL) was stirred at reflux (oil bath, 130° C.) for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo partially and then lyophilized overnight to give a white solid. The solid was treated with dichloromethane (20 mL) followed by N,N-diisopropylethylamine (11.45 mmol) and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. and propionyl chloride (5.76 mmol) was added. The reaction was allowed to warm to room temperature and the reaction was stirred at room temperature for 2 h. The reaction was quenched with water (100 mL) and 1N HCl solution (10 mL), stirred for 10 min, and then acidified to pH˜5 using 1N aq HCl. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over magnesium sulphate, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-7% methanol/ethyl acetate) afforded 4-(4-bromophenyl)-2-propanoyl-5-[(1-propanoyl-3-azetidinyl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one as a pale yellow solid (660 mg) and the title compound as an ivory solid (341 mg, 60% pure, 10% yield). MS(ES)+ m/e 365.0, 366.8 [M+H]+.
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].C[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([NH:26][C:27]([C:29]4([C:32]([NH:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)=[O:33])[CH2:31][CH2:30]4)=[O:28])=[C:21]([F:42])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[C:9]([CH3:43])=[N:8]1.[CH3:44]S(O)(=O)=O>C1COCC1.CCOCC>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[CH3:44][N:8]1[C:9]([CH3:43])=[C:10]([C:12]2[CH:17]=[C:16]([O:18][C:19]3[C:24]([F:25])=[CH:23][C:22]([NH:26][C:27]([C:29]4([C:32]([NH:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)=[O:33])[CH2:30][CH2:31]4)=[O:28])=[C:21]([F:42])[CH:20]=3)[CH:15]=[CH:14][N:13]=2)[CH:11]=[N:7]1
Reactant: Cc1nn(C)cc1-c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1c(-c2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)cnn1C
Temperature: 25 °C
Yield: 82.5 %

Procedure:
N-(4-(2-(1,5-Dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide from Example 49 (0.081 g, 0.155 mmol) was dissolved in THF (2.5 ml) and warmed until reflux. Methanesulfonic acid (10.09 μl, 0.155 mmol) was added and the mixture cooled to RT. The mixture was slowly diluted with Et2O (5 ml). A precipitate immediately began to form upon addition. After the addition was complete, the mixture was sonicated for 20 min. The precipitate was filtered off to yield N-(4-(2-(1,5-dimethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide mesylate (79 mg, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.18 (s, 1H), 9.72 (s, 1H), 8.52 (d, 1H), 8.20-8.14 (m, 2H), 7.63-7.56 (m, 3H), 7.25 (s, 1H), 7.18-7.14 (m, 2H), 6.99-6.94 (m, 1H), 3.74 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 1.67-1.64 (m, 2H), 1.58-1.55 (m, 2H); MS (ESI) m/z: 522.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=4[O:31][CH3:32])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: COc1ccc(OC)c(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1
Yield: 50.6 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,5-dimethoxyphenyl)boronic acid (0.356 g, 1.96 mmol) generally according to the procedure described for Intermediate 184 provided 0.291 g (51%) of (±)-[7-(2,5-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([O:9][CH3:10])[C:3]=1[CH3:11].C([Li])CCC.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.O>C1COCC1.CCCCCC>[CH3:10][O:9][C:4]1[C:3]([CH3:11])=[C:2]([B:17]([OH:22])[OH:18])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: COc1ncc(C)c(I)c1C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1ncc(C)c(B(O)O)c1C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-iodo-2-methoxy-3,5-dimethylpyridine (2.0 g) in THF (40 mL) was cooled to −78° C. A 2.69 M solution of n-butyllithium in hexane (6.5 mL) was added dropwise to the solution over 10 minutes. The mixture was stirred at −78° C. for 20 minutes. Triisopropyl borate (5.26 mL) was added dropwise to the mixture over five minutes. The mixture was stirred with warming to 20° C. over 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The aqueous layer was neutralized with citric acid. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was then concentrated under reduced pressure. The residue was triturated by adding MTBE. The precipitated solid was collected by filtration. This solid is called first crop. The filtrate was concentrated under reduced pressure. The residue was triturated by adding MTBE. The precipitated title compound (551 mg) was collected by filtration. The first crop were suspended in ethyl acetate. Trituration was performed by adding a small amount of MTBE. The precipitated title compound (553.3 mg) was collected by filtration. The filtrate was concentrated under reduced pressure. The residue was triturated by adding MTBE. The precipitated title compound (121:1 mg) was collected by filtration. The combined title compound (1.23 g) was obtained.