Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[N:13]2[C:14]3[N:5]([C:6](=[O:16])[CH:7]=[N:8][C:9]=3[CH:10]=[CH:11][C:12]2=[O:15])[CH2:4]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cnc2ccc(=O)n3c2n1C[C@H]3CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1Cn2c(=O)cnc3ccc(=O)n1c32
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 103.3 %

Procedure:
(1S)-1-(Hydroxymethyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (750 mg, 3.42 mmol) was suspended in dry DCM (100 ml) at room temperature under argon and then treated with Et3N (0.572 ml, 4.11 mmol). The mixture was then cooled using an ice-water bath. Methanesulfonyl chloride (0.293 ml, 3.76 mmol) was then added and the reaction was allowed to warm up to room temperature. After 50 minutes there was no starting material left so the mixture was washed with saturated NaHCO3 (100 ml). The aqueous layer was extracted with 20% MeOH/DCM (2×100 ml); the combined organic extracts were dried over MgSO4, filtered and evaporated to afford the product as a brown foam (1.05 g, 90% purity by LCMS).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:26](Br)[C:27]#[CH:28]>>[CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:28][C:27]#[CH:26])[CH2:4]1
Reactant: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCNC1
Reactant: C#CCBr
Product: C#CCN1CCC(OC)(c2cccc(OCc3ccc4ccccc4c3)c2)C1
Yield: 11 %

Procedure:
Using an analogous procedure to that described in Example 3, 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine was reacted with prop-2-ynyl bromide to give 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]-1-(prop-2-ynyl)pyrrolidine, m.p. 63°-65° C., in 11% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH:21]([OH:27])[CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH:21]([OH:27])[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Yield: 99 %

Procedure:
A solution of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-3,5-dihydroxy-6-heptenoate (34.8 g, 81.8 mmole), 1 N sodium hydroxide (82 ml, 82 mmole) and ethanol (200 ml) was stirred at 25° C. for 15 min. The reaction solution was acidified with 6 N hydrochloric acid, diluted with water (400 ml) and extracted with ether (3×200 ml). The combined organic extracts were washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as an orange oil (33.3 g, 99%); pmr (CDCl3) δ2.47 (2H, d), 4.30 (2H, br m), 4.98 (2H, s), 7.30 (5H, s).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:10])=[O:9])[N:3]=1.[C:18](O)(=O)/[C:19](=[C:21](\C=O)/Cl)/[Cl:20]>CN(C=O)C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:8]([NH:7][C:4]1[N:3]=[C:2]2[N:1]=[CH:18][C:19]([Cl:20])=[CH:21][N:6]2[N:5]=1)(=[O:9])=[O:10]
Reactant: Nc1nc(NS(=O)(=O)c2ccccc2Cl)n[nH]1
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nc2ncc(Cl)cn2n1)c1ccccc1Cl
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A mixture of 2.46 g (9.00 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2-chlorobenzenesulfonamide and 1.67 g (9.90 mmol) of mucochloric acid in 20 ml of DMF was heated to reflux for 16.5 hours. After cooling to room temperature, the solvent was removed by evaporation at reduced pressure and the residue was treated with 20 ml of 0.5N NaOH. After stirring vigorously for ~30 minutes the mixture was filtered through celite and the filtrate was acidified with 2N HCl. The solid which separated was collected by filtration, washed with water and recrystallized from acetic acid--water to yield 0.70 g (23 percent) of the desired product as a light brown solid, mp 256.5°-260.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: C[O:2][C:3](=[O:49])[C@@H:4]([NH:26][C:27](=[O:48])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:38][CH:37]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[C:39]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:41][C:36]([CH2:35][O:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([NH:26][C@@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)[C:3]([OH:49])=[O:2])=[O:48])=[CH:37][CH:38]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1)NC(=O)c1ccccc1OCc1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1)C(=O)O)c1ccccc1OCc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
(S)-2-[2-(biphenyl-4-ylmethoxy)-benzoylamino]-3-[4-(biphenyl-4-ylmethoxy)-phenyl]-propionic acid methyl ester (50 mg, 0.077 mmol) was dissolved in 5 mL of THF-MeOH (4-1), cooled to 0° C. and 1.1 equiv of 2 N LiOH added. After 30 minutes, 3.2 additional equiv of 2N LiOH was added and the reaction stirred for 30 minutes. The reaction was worked up according to Procedure C to give 29 mg of the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:24])[CH3:23].C(OCC)(=O)C>CN(C)C(=O)C>[C:22]([NH:21][NH:20][C:18]([C:15]1[CH:16]=[CH:17][C:12]2[N:11]=[CH:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[CH:14]=1)=[O:19])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CSc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CSc1ccc(-n2cnc3ccc(C(=O)NNC(C)=O)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-[4-(methylthio)phenyl]-1H-benzimidazole-6-carbohydrazide (1.0 g, 3.35 mmol) in N,N-dimethylacetamide (5 mL) was added acetyl chloride (262 μL, 3.69 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. Ethyl acetate was added to the reaction mixture, the precipitate was collected by filtration and washed with ethyl acetate to give the title compound (1.14 g, yield 100%) as colorless crystals.
Reaction SMILES: [Br:1][CH:2]([C:6]1[C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][N:7]=1)C(O)=O>C1(C)C=CC=CC=1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]2[O:8][N:7]=[C:6]([CH2:2][Br:1])[C:10]=2[CH:11]=1
Reactant: O=C(O)C(Br)c1noc2ccc(Cl)cc12
Solvent: Cc1ccccc1
Product: Clc1ccc2onc(CBr)c2c1
Temperature: 96 °C

Procedure:
A suspension of alpha-bromo-5-chloro-1,2-benzisoxazole-3-acetic acid (3.39 Kg, 11.7 moles) in toluene (12 L) is heated at 96° C. for 18 hours. The solution is cooled to room temperature and washed with water (2×4 L), saturated sodium bicarbonate solution (2×4 L) and water (2×4 L) before drying over anhydrous sodium sulfate (1 Kg) and filtering. The filtrate is evaporated in vacuo to afford the crude 5-chloro-3-bromomethyl-1,2-benzisoxazole, m.p. 83°-85° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:38]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:41][C:42]1[N:46]([CH3:47])[CH:45]=[N:44][N:43]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH2:41][C:42]5[N:46]([CH3:47])[CH:45]=[N:44][N:43]=5)=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:38]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CCC)cc1
Reactant: Cn1cnnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nncn4C)cc2)CCN3CCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.3 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-N-(4-hydroxyphenyl)-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.62 g), 3-chloromethyl-4-methyl-4H-1,2,4-triazole hydrochloride (0.24 g) and potassium carbonate (0.5 g), N,N-dimethylformamide (15 ml) was added and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol/triethylamine), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(4-methyl-4H-1,2,4-triazol-3-yl) methoxy]phenyl]-1-propyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 24) (0.48 g) as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40]N)=[CH:36][CH:35]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:40][C:37]2[C:38]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2
Reactant: Cc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3F)CC2)c1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccccc3F)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([OH:10])[C:5]=1[N+:11]([O-:13])=[O:12].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6](=[O:10])[C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1c(Cl)ccnc1O
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Temperature: 60 °C

Procedure:
Sodium hydride (60% dispersion in mineral oil, 7.5 g, 0.188 mol) was added to a stirred solution of 4-chloro-2-hydroxy-3-nitropyridine (23.68 g, 0.126 mol) in THF (250 mL) at 0° C. After 25 min ethyl bromoacetate (16.7 mL, 0.151 mol) was added and the reaction was warmed to 60° C. After 20 h the reaction was cooled and washed with brine acidified with 1M HCl. The organic layer was dried (Na2SO4) and evaporated in vacuo to a solid which was recrystallised from ethyl acetate/hexanes to give the title compound;
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([B:20]([OH:22])[OH:21])=[CH:16][C:15]=1[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:13])(=[O:10])=[O:9])(=O)C>Cl.CO>[CH:23]1([C:15]2[CH:16]=[C:17]([B:20]([OH:21])[OH:22])[CH:18]=[CH:19][C:14]=2[C:12]([NH:11][S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:10])=[O:9])=[O:13])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(B(O)O)cc1C1CCCC1
Agent: Cl
Solvent: CO
Product: O=C(NS(=O)(=O)CCCO)c1ccc(B(O)O)cc1C1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 107.7 %

Procedure:
[4-[[[[3-(Acetyloxy)propyl]sulfonyl]amino]carbonyl]-3-cyclopentylphenyl]boronic acid (3.28 g) was dissolved in 2.5N hydrogen chloride in methanol (20 ml) and the mixture was stirred at room temperature for 17 hours. The solvent was removed by evaporation to give [3-cyclopentyl-4-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]phenyl]boronic acid (3.16 g) as a brown solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[N:15]=1.C(N(CC)CC)C.Cl[C:31]1[S:32][CH:33]=[CH:34][N:35]=1>CS(C)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:22])=[N:12][CH:13]=[C:14]([C:16]2[CH2:17][CH2:18][N:19]([C:31]3[S:32][CH:33]=[CH:34][N:35]=3)[CH2:20][CH:21]=2)[N:15]=1
Reactant: Clc1nccs1
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nc2ccccc2[nH]1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1ncc(C2=CCN(c3nccs3)CC2)nc1-c1nc2ccccc2[nH]1
Temperature: 160 °C
Yield: 28.5 %

Procedure:
A solution of 3-(1H-benzo[d]imidazol-2-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (100 mg, 0.1922 mmol) in DMSO (2.000 mL) was treated with triethylamine (58.35 mg, 80.37 μL, 0.5766 mmol) and 2-chlorothiazole (27.57 mg, 0.2306 mmol) and heated in the microwave for 40 minutes at 160° C. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound (20.6 mg, 15% Yield). 1H NMR (400.0 MHz, DMSO) d 2.89 (s, 2H), 3.80 (t, J=5.7 Hz, 2H), 4.21 (d, J=2.5 Hz, 2H), 6.86 (s, 1H), 6.94-6.96 (m, 1H), 7.28-7.31 (m, 3H), 7.69 (s, 2H) and 8.41 (s, 1H) ppm; MS (ES+) 376.0
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[OH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](O)=[O:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[OH:9][CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:12]
Reactant: Cc1ccc(N)nc1
Reactant: CC(C)C(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C(O)C(C)C)nc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 14.2 %

Procedure:
5-Methylpyridin-2-amine (CAS 1603-41-4) (2.014 g, 18.6 mmol) was added in one portion to 2-hydroxy-3-methylbutanoic acid (CAS 4026-18-0) (2.0 g, 16.9 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (7.08 g, 18.6 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.80 mL, 33.9 mmol) in DCM (40 mL). The resulting suspension was stirred at ambient temperature for 70 hours. The reaction mixture was concentrated, diluted with EtOAc (150 mL) and washed sequentially with water (150 mL) and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane to afford 2-hydroxy-3-methyl-N-(5-methylpyridin-2-yl)butanamide (500 mg).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[C:20]([O:27][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[O:18][C:17](=[O:33])[CH:16]=1)[C:9]([O:11]C)=[O:10].CO>C1COCC1>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([C:13]=1[NH:14][C:15]1[C:24]2[C:19](=[C:20]([O:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:25][CH3:26])=[CH:22][CH:23]=2)[O:18][C:17](=[O:33])[CH:16]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)c1cncc(Cl)c1Nc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Nc3c(Cl)cncc3C(=O)O)cc(=O)oc2c1OC1CCCC1
Reaction time: 3 h

Procedure:
Lithium hydroxide (1 mL, 1M, 1 mmol) was added to a solution of methyl 5-chloro-4-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)nicotinate, MeOH (0.8 mL), and THF (1.2 mL). The mixture was stirred for 3 h, quenched with 1N HCl (3 mL), and extracted with EtOAc. The organic extract was dried, filtered, concentrated and purified by reverse-phase HPLC (25→100% MeCN/H2O) to give 5-chloro-4-(8-(cyclopentyloxy)-7-methoxy-2-oxo-2H-chromen-4-ylamino)nicotinic acid: 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 7.85 (d, 1H), 7.19 (d, 1H), 4.83 (m, 1H), 4.74 (s, 1H), 3.90 (s, 3H) 1.85-1.54 (m, 8H); MS (ESI): 430.9.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][C:16]([OH:18])=O)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33]>O1CCCC1>[CH3:31][S:32]([NH:35][C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1)(=[O:34])=[O:33]
Reactant: O=C(O)Cc1ccc2c(c1)Nc1nccnc1S2
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)Cc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.5 %

Procedure:
To a solution of 0.259 g of (10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetic acid in tetrahydrofuran (10 ml) was added in a nitrogen atmosphere 0.18 g of carbonyldiimidazole and the resulting mixture was heated under reflux for 30 minutes. Then the reaction mixture was brought back to room temperature and 0.285 g of methanesulfonamide was added thereto. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.163 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Yield: 8 %

Procedure:
By far the most studied and useful cyclotrimerization catalysts have been of the η5-cyclopentadienyl cobalt (CpCo) family. In 1967, Yamazaki and Hagihara isolated the first cobalt cyclopentadiene triphenylphosphine complex (CpCoP(Ph)3), which when treated with a stoichiometric amount of diphenylacetylene in refluxing toluene produced hexaphenylbenzene in 8% yield after one hour. (Yamazaki and Hagihara (1967) J. Organomet. Chem. 7:22). Cobalt cyclopentadiene dicarbonyl (CpCo(CO)2) (5), a commercially available catalyst, reacts catalytically with bis-alkynes (6) in refluxing n-octane to form several bicyclic systems (7), including benzocyclobutenes (n=2) in 45% yield. (Vollhardt and Bergman (1974) J. Am. Chem. Soc 96:4996).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][C@H:6]([CH3:17])[N:7]3[C:8]([C@@H:14]([NH2:16])[CH3:15])=[N:9]2.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23](Cl)[N:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([NH:16][C@H:14]([C:8]2[N:7]3[C:13]4[C:3]([O:4][CH2:5][C@@H:6]3[CH3:17])=[C:2]([F:1])[CH:12]=[CH:11][C:10]=4[N:9]=2)[CH3:15])[N:22]=[CH:21][N:20]=1
Reactant: C[C@H](N)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Temperature: 100 °C
Yield: 78.6 %

Procedure:
A mixture of (S)-1-((S)-6-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (86 mg, 0.36 mmol), 4-amino-6-chloro-5-cyanopyrimidine (56 mg, 0.36 mmol) and DIPEA (125 μL, 0.92 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting brown residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in DCM) to afford 440 as a white solid (100 mg, 79%). LCMS (Method K): RT 2.86 min [M+H]+ 354.1. 1H NMR (DMSO, 400 MHz): δ 8.01 (1H, s), 7.08 (1H, dd, J=8.8, 3.1 Hz), 6.94 (1H, dd, J=12.3, 8.8 Hz), 5.67 (1H, q, J=7.0 Hz), 5.04 (1H, qdd, J=6.6, 2.6, 1.7 Hz), 4.47 (1H, dd, J=11.9, 1.7 Hz), 4.20 (1H, dd, J=11.9, 2.6 Hz), 1.71 (3H, d, J=7.0 Hz), 1.45 (3H, d, J=6.6 Hz)
Reaction SMILES: [OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5](=[O:28])[C:6]1[C:19]([I:20])=[C:18]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[C:17]([I:26])=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[C:7]=1[I:27].[CH2:31]1[O:33][CH2:32]1.Cl>O>[OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5](=[O:28])[C:6]1[C:19]([I:20])=[C:18]([N:21]([CH2:31][CH2:32][OH:33])[C:22](=[O:25])[CH2:23][Cl:24])[C:17]([I:26])=[C:8]([C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10])[C:7]=1[I:27]
Reactant: O=C(CCl)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: C1CO1
Agent: Cl
Solvent: O
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N(CCO)C(=O)CCl)c1I

Procedure:
The general procedure for the process of the invention involves reacting 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with N,N-dimethylacetamide and chloroacetyl chloride. The resulting product is hydrolyzed with a base (such as sodium hydroxide). A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. Alternately, 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide is reacted with N,N-dimethylacetamide, acetonitrile, and chloroacetyl chloride. The resulting product is hydrolyzed with a base. A homogeneous solution is obtained by adding water. Precipitation is affected to yield N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide. This product is combined with an aqueous base and deionized water. 2-Chloroethanol is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. Alternately, N,N′-bis(2,3-dihydroxypropyl)-5-(2-chloroacetamido)-2,4,6-triiodoisophthalamide plus metal halide and deionized water are combined. Ethylene oxide is added followed by heating. The addition of hydrochloric acid yields N,N′-bis(2,3-dihydroxypropyl)-5-[N-(2-hydroxyethyl)(2-chloroacetamido)]-2,4,6-triiodoisophthalamide. This product is suspended in water with acetate ions and hydrochloric acid added. This suspended solution can take place at or above atmospheric pressure. Generally about 1 to about 2 atmospheres above atmospheric pressure is used. After adding aqueous sodium hydroxide to, maintain the pH, the reaction yields N,N′-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiodoisopthalamide. Finally, salts and low molecular weight impurities are removed.