Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Br[CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1>CN(C)C=O>[C:1]([O:9][CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(CBr)O1
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(COC(=O)c2ccccc2)O1
Temperature: 150 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
Then, sodium benzoate (50.44 g, 0.35 mol) were added to a mixture of 4-bromomethyl-2,2-dimethyl-1,3-dioxolane (58.52 g, 0.3 mol) and N,N-dimethylformamide (500 ml) and the resulting mixture was stirred for 15 hours at 150° C. After cooling the salt was filtered and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo to give 64.5 g of crude 4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH:12](=[O:14])[CH3:13]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH:13][CH:12]=[O:14])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CC=O
Product: O=CC=Cc1cccc([N+](=O)[O-])c1

Procedure:
3-nitro cinnamaldehyde was prepared by Claisen-Schmidt condensation of 3-nitrobenzaldehyde with acetaldehyde as follows.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[CH:22]=[N:23][C:24](S(C)(=O)=O)=[N:25][CH:26]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:19][C:17]1[CH:18]=[C:13]2[C:12]([CH2:20][C:21]3[CH:26]=[N:25][C:24]([NH:37][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[N:23][CH:22]=3)=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1
Reactant: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Reactant: NC1CCCCC1
Product: Clc1cnc2[nH]cc(Cc3cnc(NC4CCCCC4)nc3)c2c1

Procedure:
[5-(5-Chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexyl-amine P-3001 is prepared in one step from 1-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-1H-pyrrolo[2,3-b]pyridine 37 and cyclohexanamine 62 as shown in Scheme 9.
Reaction SMILES: ClS([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=O)=O>N1C=CC=CC=1.C(Cl)Cl>[C:9]([OH:11])(=[O:10])[C:8]1[CH:12]=[CH:13][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
To a stirred solution of compound 757-A (4.99 g, 25.0 mmol) in pyridine (50 mL) and methylene chloride (25 mL), cooled on an ice bath, was added 4-(chlorosulfonyl)benzoic acid (5.52 g, 25.0 mmol), portion-wise, for 4 min, and the reaction was allowed to stir at ambient temperature for 4 days. The reaction mixture was concentrated under reduced pressure, the residue stirred with 1N HCl (100 mL), the resulting solid filtered, washed with 1N HCl and air dried. The crude product was triturated with MeOH (15 mL), filtered, rinsed with MeOH (2×5 mL) and air-dried to afford crude benzoic acid (not shown). The benzoic acid was suspended in MeOH (100 mL), treated with concentrated H2SO4 (0.1 mL) and the reaction mixture refluxed for 5 days. The reaction mixture was cooled, the solvent evaporated under reduced pressure, and the residue was triturated with MeOH (15 mL), filtered, washed with methanol (2×5 mL) and once with another portion of methanol (10 mL). The solid was dried to afford 6.31 g of compound 398-A as a tan-yellow powder. 1H-NMR (DMSO-d6) δ: 2.02 (s, 3H), 3.89 (s, 3H), 7.40-7.29 (m, 2H), 7.67-7.61 (m, 1H), 7.83-7.77 (m, 1H), 7.89 (d, 2H), 8.14 (d, 2H), 10.66 (s, 1H); MS: m/z 360.2 (M-H+).
Reaction SMILES: [OH:1]/[N:2]=[CH:3]/[C:4]1[N:5]2[C:9]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=1)=[CH:8][CH:7]=[CH:6]2.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[Cl:31]>C1COCC1>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[N:5]4[C:9]([C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=3)=[CH:8][CH:7]=[CH:6]4)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[Cl:31]
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(/C=N/O)n2cccc12
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n2cccc12
Temperature: 68 °C
Yield: 10.4 %

Procedure:
A solution of crude (E)-methyl 5-((hydroxyimino)methyl)indolizine-8-carboxylate (300 mg, 1.37 mmol) in THF (20 mL) was added to a stirred solution of DIB (882 mg, 2.74 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (750 mg, 2.74 mmol) in THF (15 mL) at rt. The mixture was heated at 68° C. for 2 h. The solvent was removed under reduced pressure and the crude product was purified by prep-TLC and then Combiflash to give methyl 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylate (70 mg, yield 10%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH:63]([C@@H:76]1[CH2:80][CH2:79][CH2:78][NH:77]1)([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CS(C)=O>[CH:63]([C@@H:76]1[CH2:80][CH2:79][CH2:78][N:77]1[C:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5]([NH:15][CH:16]([C:18]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=4[N:19]=3)[CH3:17])=[N:6][CH:7]=[N:8]2)=[CH:3][C:2]=1[Cl:1])=[O:13])([C:70]1[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CCCN2)cc1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3C(c3ccccc3)c3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-benzhydryl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].[Cl-:15].[Ca+2].[Cl-].O>CS(C)=O>[Cl:15][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(C(F)(F)F)ccc(F)c1F
Reactant: [Cl-]
Agent: [Ca+2]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1c(C(F)(F)F)ccc(F)c1Cl
Temperature: 145 °C
Reaction time: 6 h
Yield: 70.8 %

Procedure:
To a solution of 50.9 g of 2,3-difluoro-6-trifluoromethylbenzonitrile in 240 ml of dimethyl sulfoxide (DMSO) was added 53.3 g of calcium chloride and the mixture was stirred for 6 hours at a temperature of from 140 to 150° C. After cooling, the reaction mixture was further added with 240 ml water and extracted with 240 ml and 100 ml hexane twice. The organic layer obtained was dried over anhydrous magnesium sulfate, and the solvent therein was distilled under reduced pressure. The crude product obtained was distilled under reduced pressure to obtain 38.9 g of the title compound.
Reaction SMILES: CC(C)([O-])C.[K+].N[CH:8]=[CH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].CO[CH:18](OC)[CH2:19][C:20]#[N:21].Cl>C(COC)OC>[F:12][C:11]([F:14])([F:13])[C:10](=[O:15])[CH:9]=[CH:8][CH:18]=[CH:19][C:20]#[N:21]
Reactant: NC=CC(=O)C(F)(F)F
Reactant: COC(CC#N)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Product: N#CC=CC=CC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a three-necked flask, 61.6 g (0.55 mol) of potassium tert-butoxide were introduced into 250 ml of dimethoxyethane under N2 and the solution was cooled to 0° C. 4-Amino-1,1,1-trifluoro-3-buten-2-one, 69.5 g (0.5 mol), was added dropwise at this temperature in the course of 30 min and then 60.3 g (0.525 mol) of 3,3-dimethoxypropionitrile were added dropwise. The mixture was then stirred at 30° C. for 3-4 h. The reaction mixture was added to ice and acidified to pH 3-4 using HCl. The precipitate was filtered off and washed with water. 71 g of product (75%), mp: 123-126° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7](I)[C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(O)c1c(I)ccnc1Cl
Product: Cc1ccccc1-c1ccnc(Cl)c1C(=O)O
Yield: 89.6 %

Procedure:
In a similar manner to Reference Example 5,2-chloro-4-iodonicotinic acid (compound of Reference Example 1; 5.67 g) was reacted with 2-methylphenylboronic acid (3.00 g) to obtain 2-chloro-4-(2-methylphenyl)nicotinic acid (4.44 g, 90%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][NH:25][C:24]=1/[CH:23]=[C:12]1\[C:13](=[O:22])[NH:14][C:15]2[C:11]\1=[C:10]([C:2]#[C:1][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: C#Cc1cccnc1
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
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#Cc3cccnc3)c21

Procedure:
Using Method D above, 3-ethynyl pyridine (0.14 g, 1.38 mmol) (see Example 64) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (0.2 g, 0.55 mmol) (Starting Material 3) using (Ph3P)4Pd (31.8 mg) (Aldrich) and CuI (5.3 mg) (Aldrich) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent and at 85° C. for 18 h, yielding (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 0.16 g, 71%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12]/[C:13](=[N:16]/[H])/[NH:14][OH:15])[C:7]([CH2:18][CH2:19][CH3:20])=[CH:6]2)#[N:2].[F:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:25][C:26]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:27]=1[C:28]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:21]([F:24])([F:23])[F:22])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:18][CH2:19][CH3:20])[N:16]=1
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(C(F)(F)F)c(C#N)ccc21)NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)ccc2F)n1
Temperature: 150 °C
Yield: 42.2 %

Procedure:
To a solution of (1Z)-2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (0.050 g, 0.154 mmol) in anhydrous acetonitrile (2.0 mL) under N2, was added 2,5-difluorobenzoyl chloride (0.121 g, 0.177 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.029 g (42% yield) of pure product: MS (ES) m/z 446 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](F)(=[O:31])=[O:30])=[CH:25][C:24]=1[NH2:33].[I-].C([NH3+])(C)(C)C>ClCCl>[NH2:33][C:24]1[CH:25]=[C:26]([S:29]([O:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:31])=[O:30])[CH:27]=[CH:28][C:23]=1[O:22][CH3:21]
Reactant: COc1ccc(S(=O)(=O)F)cc1N
Reactant: COc1cc(O)cc(OC)c1OC
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Oc2cc(OC)c(OC)c(OC)c2)cc1N
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution of 3,4,5-trimethoxyphenol (505.7 mg, 2.75 mmol) in dichloromethane (28 mL) was treated sequentially with triethylamine (1.2 mL), 4-methoxymetanilyl fluoride (572.5 mg, 2.75 mmol), and tert-butylammonium iodide (106 mg, 0.287 mmol), stirred overnight, and washed once with 1M Na2CO3. The organic layer was separated, dried (MgSO4), filtered, and concentrated. Chromatography of the concentrate on silica gel with 40% ethyl acetate/hexanes provided 356 mg of the desired compound.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]2[CH2:15][C@@H:14]([C:16]3[N:20]4[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]4=[CH:18][N:17]=3)[CH2:13]2)(=O)=O)=CC=1.C1(C)C=CC(S(OC[C@H]2C[C@H](C3N4C=CN=C(Cl)C4=CN=3)C2)(=O)=O)=CC=1.[C:53]([Si:57](Cl)([CH3:59])[CH3:58])([CH3:56])([CH3:55])[CH3:54]>>[Si:57]([O:10][CH2:11][C@@H:12]1[CH2:13][C@H:14]([C:16]2[N:20]3[CH:21]=[CH:22][N:23]=[C:24]([Cl:25])[C:19]3=[CH:18][N:17]=2)[CH2:15]1)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:59])[CH3:58]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3ncc4c(Cl)nccn43)C2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@H](c3ncc4c(Cl)nccn43)C2)cc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](c2ncc3c(Cl)nccn32)C1

Procedure:
cis-3-[3-(tert-Butyldimethylsilanyloxymethyl)cyclobutyl]-8-chloroimidazo[1,5-a]pyrazine and trans-3-[3-(tert-butyldimethylsilanyloxymethypcyclobutyl]-8-chloroimidazo[1,5-a]pyrazine were prepared according to the general procedure for the preparation for cis-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate and trans-3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutylmethyl toluene-4-sulfonate, except tert-butylchlorodimethylsilane was used instead of p-toluenesulfonic anhydride.
Reaction SMILES: Cl.[NH:2]([CH2:9][C:10]([O:12]CC)=O)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-:15][C:16]#[N:17].[K+]>>[O:15]=[C:16]1[NH:17][C:10](=[O:12])[CH2:9][N:2]1[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)CN1CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
Concentrated hydrochloric acid (24.0 mL) was gradually dropped into 350 mL of an aqueous solution containing 27.5 g of diethyl iminodiacetate and 23.3 g of potassium cyanate. After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo. The residue was extracted with ethyl acetate several times and the extracts were combined followed by drying over sodium sulfate. The dried extract was concentrated and the residue was recrystallized from ethanol to give 11.1 g of ethyl 2,4-dioxoimidazolidine-1-acetate as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[C:13](N)(=[NH:15])[CH3:14]>C(OCCO)C>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:13]([CH3:14])[N:15]=[C:4]2[OH:6]
Reactant: CC(=N)N
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: Cl
Solvent: CCOCCO
Product: Cc1nc(O)c2cc(Cl)ccc2n1
Yield: 38.6 %

Procedure:
2-Amino-5-chlorobenzoic acid (3.58 g, 20.9 mmol, 1 eq.), acetamidine hydrochloride (2.36 g, 25.1 mmol, 1.2 eq.) and 2-ethoxyethanol (70 mL) were mixed and refluxed for 48 h. The resultant solids were filtered and dried to yield 1.57 g of yellow solid product. MS (ES+)=195/197 (M+H)++.
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].S(Cl)([Cl:13])=O>CCCCCC.N1C=CC=CC=1>[C:1]([Cl:13])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: CCCCCC
Solvent: c1ccncc1
Product: O=C(Cl)c1ccccc1O

Procedure:
Salicylic acid (5.0 g, 36.2 mmol) was suspended in dry hexane (40 ml) and thionyl chloride (4.52 g, 38 mmol) was added under nitrogen atmosphere followed by one drop of pyridine. The mixture was refluxed for two hours while stirring. The clear yellow solution was cooled and concentrated in vacuum, giving a dense oil to be used in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[NH:22]1[CH:26]=[C:25]([CH2:27][C:28](O)=[O:29])[N:24]=[N:23]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:22]1[CH:26]=[C:25]([CH2:27][C:28]([NH:1][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[O:11])[CH2:6][CH2:5]2)=[O:29])[N:24]=[N:23]1
Reactant: NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)Cc1c[nH]nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]nn1)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 4-(2-aminoethyl)piperidine-1-carboxylate (Example 3, step 1) (100 mg, 0.302 mmol), 2-(1H-1,2,3-triazol-4-yl)acetic acid (57.6 mg, 0.453 mmol), 1-propanephosphonic anhydride solution (0.353 mL, 0.604 mmol) and Huenig's Base (0.105 mL, 0.604 mmol) in DMF (1 mL) was stirred at room temperature for 18 hours, and then concentrated under reduced pressure. The mixture was diluted with water and extracted with EtOAc. The organic portion was dried over MgSO4, filtered and the solvent concentrated under pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound;
Reaction SMILES: O=[C:2]([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[O:12][C:13](=[O:14])[C:6]=2[CH2:5]1.[CH2:20]([NH2:22])[CH3:21].S([O-])([O-])(=O)=O.[Ca+2].C(O)(=O)C>O1CCCC1>[CH2:20]([NH:22][CH:2]([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[O:12][C:13](=[O:14])[C:6]=2[CH2:5]1)[CH3:21]
Reactant: CC(=O)CN1CCc2c(c(=O)oc3ccccc23)C1
Reactant: CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNC(C)CN1CCc2c(c(=O)oc3ccccc23)C1
Temperature: 40 °C
Yield: 51.6 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (18.2 g, 0.071 moles), ethylamine (10 ml, 0.153 moles), anhydrous calcium sulfate (15 g), and glacial acetic acid (1 ml) in tetrahydrofuran (450 ml) is shaken at 40° C. in a pressure vessel. After 18 hours the mixture is cooled and filtered. The filtrate is hydrogenated at 25° C. and 50 psi in the presence of 10% platinum or carbon until hydrogen uptake ceases. The catalyst is removed by filtration, and the filtrate is evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate gave the product (10.5 g), mp 104°-105° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[N:4][CH:3]=1.[CH2:13]([Li])CCC.IC.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][CH:10]2[CH2:11][CH2:12]2)[CH3:13])[CH:5]=[N:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Clc1cncc(NCC2CC2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(CC1CC1)c1cncc(Cl)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
To a solution of 6-chloro-N-(cyclopropylmethyl)pyrazin-2-amine (0.60 g) in tetrahydrofuran (5 mL) was added dropwise n-butyllithium (3.06 mL, 1.6 M hexane solution) at −78° C. The mixture was stirred at −78° C. for 5 min, and iodomethane (1.02 mL) was added dropwise thereto. The mixture was stirred at −78° C. for 30 min, and further stirred at 0° C. for 1 hr. Saturated aqueous sodium thiosulfate solution (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→15% ethyl acetate/hexane) to give the title compound (0.46 g, 70%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][CH2:19][CH2:18][C:17]2=[O:24].Cl>CCOCC>[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][CH2:19][CH:18]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[C:17]2=[O:24]
Reactant: O=C1CCOc2ccc(F)cc21
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2cc(F)ccc2OCC1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 50.6 %

Procedure:
Ethyl trifluoroacetate (4.33 g, 30 mmol) was dissolved in ether (25 mL) and treated with sodium methoxide (25%, 7.08 g, 33 mmol). To the stirred solution was added 6-fluoro-4-chromanone (4.92 g, 30 mmol) and additional ether (10 mL). The reaction was stirred at room temperature overnight (19.0 hours) and treated with 3N hydrochloric acid (15 mL). The organic layer was collected, washed with brine, dried over MgSO4, concentrated in vacuo and recrystallized from ether/hexane to give a yellow solid (3.98 g, 51%): mp 107°-112° C.; 1H NMR (CDCl3) 300 MHz 14.95 (s, 1H) 7.52 (dd, 1H) 7.23 (m, 1H) 6.97 (m, 1H) 5.07 (s, 2H); 19F NMR (CDCl3) 300 MHz -72.60 (s), -119.93 (m). Mass spectrum: M+=262.
Reaction SMILES: C(OC([N:8]1[CH2:15][C@H:14]2[N:16](C(OC(C)(C)C)=O)[C@H:10]([CH2:11][C:12]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]4[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=4[Cl:45])=[CH:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=O)(C)(C)C.[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][CH3:61])=[CH:54][C:48]=1[CH2:49][NH:50][CH:51]1[CH2:53][CH2:52]1>>[Cl:46][C:47]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][CH3:61])=[CH:54][C:48]=1[CH2:49][N:50]([CH:51]1[CH2:52][CH2:53]1)[C:24]([C:13]1[C@@H:14]2[NH:16][C@H:10]([CH2:11][C:12]=1[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][O:36][C:37]3[C:42]([Cl:43])=[CH:41][C:40]([CH3:44])=[CH:39][C:38]=3[Cl:45])=[CH:31][CH:32]=1)[CH2:9][NH:8][CH2:15]2)=[O:25]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(C3=C(C(=O)O)[C@H]4CN(C(=O)OC(C)(C)C)C[C@@H](C3)N4C(=O)OC(C)(C)C)cc2)c(Cl)c1
Reactant: COCCc1ccc(Cl)c(CNC2CC2)c1
Product: COCCc1ccc(Cl)c(CN(C(=O)C2=C(c3ccc(OCCOc4c(Cl)cc(C)cc4Cl)cc3)C[C@@H]3CNC[C@H]2N3)C2CC2)c1

Procedure:
This compound was synthesized from (1R,5S)-7-{4-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-phenyl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester and [2-chloro-5-(2-methoxy-ethyl)-benzyl]-cyclopropyl-amine as for compound L1, and then Example 1. MS (ESI, Q+) m/z 686.1.