Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[N:4]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([C:23]4[N:27]=[N:28][NH:29][N:24]=4)=[CH:25][CH:26]=3)[N:8]=2)[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1cc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)ccc1-c1nn[nH]n1
Temperature: 120 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A mixture of 4-(4,6-dimorpholino-1,3,5-triazin-2-yl)benzonitrile (11 mg, 0.031 mmol), sodium azide (5.5 mg, 0.085 mmol) and triethylamine hydrochloride (6.0 mg, 0.043 mmol) in 2 mL of DMF was stirred at 120° C. for 6 hr. Then the reaction mixture was cooled to room temperature and purified by reverse phase chromatography to give 2,4-dimorpholin-4-yl-6-[4-(2H-tetrazol-5-yl)phenyl]-1,3,5-triazine. Yield 12 mg, 97% yield; HPLC: Rt=2.09 min; MS 394 [M−H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[C:40]([C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][C:47]=1[F:48])#[N:41].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[C:40]([C:42]1[CH:43]=[C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)[CH:45]=[CH:46][C:47]=1[F:48])#[N:41]
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(F)c(C#N)c2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 64.7 %

Procedure:
To 300.0 mg (0.49 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 12 ml toluene were added 11.4 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 97.4 mg (0.59 mmol) (3-cyano-4-fluoro-phenyl)boronic acid in 3.0 ml ethanol and 88.7 mg (1.53 mmol) potassium fluoride in 3.0 ml water. The mixture was stirred at 100° C. for 3 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 206 mg (58%) tert-butyl 4-{3-[(3R)-3-({1-[5-(3-cyano-4-fluorophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:24](=[O:30])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5]
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: O=C1CCC(=O)O1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCC(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 27.4 %

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (298 mg) in dimethylformamide (4 ml) was added succinic anhydride (94 mg), and the mixture was stirred at ambient temperature for 12 hours. To the mixture was added water (10 ml) and the precipitate was collected. The solid was treated with hot ethanol (5 ml), allowed to cool to ambient temperature, filtered and washed with water to give 8-(2,6-dichlorobenzoylamino)-4-[2-(3-carboxypropanoyl)hydrazino]quinoline as a yellow crystal (105 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[Cl:49][C:50]1[CH:55]=[CH:54][C:53]([S:56][CH2:57][CH2:58]CO)=[C:52]([CH3:61])[CH:51]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:58][CH2:57][S:56][C:53]2[CH:54]=[CH:55][C:50]([Cl:49])=[CH:51][C:52]=2[CH3:61])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Cl)ccc1SCCCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCSc4ccc(Cl)cc4C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 73.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (73 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[4-chloro-2-methylphenyl]sulfanyl-1-propanol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (98 mg, yield 69%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][CH:11]1[CH2:14][CH2:13][CH2:12]1.[C:15]12([C:25](O)=[O:26])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[CH:11]1([CH2:10][N:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5]/[C:4]/2=[N:8]\[C:25]([C:15]23[CH2:24][CH:19]4[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]4)[CH2:22]2)[CH2:16]3)=[O:26])[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1nc(N)sc1C
Reactant: BrCC1CCC1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: Cc1s/c(=N\C(=O)C23CC4CC(CC(C4)C2)C3)n(CC2CCC2)c1C

Procedure:
4,5-Dimethylthiazol-2-ylamine, bromomethylcyclobutane and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.60-1.75 (m, 6H) 1.75-1.93 (m, 10H) 1.92-2.06 (m, 5H) 2.15 (s, 3H) 2.18 (s, 3H) 2.64-2.74 (m, 1H) 4.22 (d, J=7.18 Hz, 2H); MS (ESI) m/z 359 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:19](Cl)(Cl)=[O:20].[Br:23][C:24]1[C:25]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)[CH:34]=2)=[CH:26][C:27]([F:31])=[C:28]([CH:30]=1)[NH2:29]>C(Cl)Cl.O>[Br:23][C:24]1[C:25]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)[CH:34]=2)=[CH:26][C:27]([F:31])=[C:28]([NH:29][C:19]([N:9]2[CH2:10][CH2:11][N:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[C:8]2=[O:12])=[O:20])[CH:30]=1
Reactant: O=C(Cl)Cl
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(N)cc3Br)ccn2)cn1
Reactant: O=C1NCCN1C1CCOCC1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCN(C5CCOCC5)C4=O)cc3Br)ccn2)cn1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
A solution of Example B1 (141 mg, 0.826 mmol) and pyridine (98 mg, 1.239 mmol) in DCM (4 mL) was added to phosgene (20% in toluene, 1.021 g, 2.065 mmol), under Ar, stirred for 15 minutes, then concentrated to dryness. The residue was treated with a solution of 5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (150 mg, 0.413 mmol) and TEA (209 mg, 2.065 mmol) in DCM (4 mL) and stirred at RT for 0.5 h. The mixture was diluted with water, extracted with EtOAc (2×) and combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford N-(5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (134 mg, 58%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (d, J=2.7 Hz, 1 H), 8.54 (d, J=8.2 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.55 (d, J=11.3 Hz, 1 H), 7.19 (d, J=2.4 Hz, 1 H), 6.61 (dd, J=5.7, 2.5 Hz, 1 H), 3.93-3.87 (m, 3 H), 3.84 (s, 3 H), 3.83-3.78 (m, 2 H), 3.47 (m, 2 H), 3.37 (m, 2 H), 1.71 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: (M+H+): 559.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.BrC1C=C2C(=CC=1)C(N[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=NC=C2>>[Br:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][N:3]=[C:2]2[NH:1][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:7][CH:8]=1
Reactant: Nc1nccc2ccc(Br)cc12
Reactant: O=C(Nc1nccc2cc(Br)ccc12)c1ccccc1
Product: O=C(Nc1nccc2ccc(Br)cc12)c1ccccc1

Procedure:
Compound 37e was prepared from 37d using the procedure described for 1e. 1H-NMR 200 MHz (CDCl3) δ: 6.98 (1H,d, J=6 Hz), 7.37-7.57 (6H, m), 8.41-8.48 (2H, m), 9.14 (1H, d, J=2 Hz).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12]CCC1CC2C(C)=C(OCC3C=CC=CC=3)C(C)=C(C)C=2O1>>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([OH:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 177.9 %

Procedure:
105 mg of p-toluenesulfonyl chloride is added to a solution of 156 mg of 2-(RS)-(2-hydroxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7 -trimethylbenzofurane in 0.5 ml cooled to 0° C. The reaction mixture is stirred for 3 hours, then it is acidified and extracted. The organic extracts are dried and evaporated, thus giving 185 mg of raw product, which is then purified with chromatography (SiO2). 153 mg of p-toluenesulfonate of 2[2,3-dihydro-5-benzyloxy-4,6,7-trimethyl-2-(RS)benzofuranyl]ethyl are obtained. IR (KBr): 1359, 1177 cm-1 (νSO2). The product thus obtained is then solubilized in 2 ml of anhydrous tetrahydrofurane and added to a suspension of 45 mg of lithium and aluminum hydride in 5 ml of anhydrous tetrahydrofurane. The reaction mixture is stirred in an inert atmosphere for 30 minutes. The reaction process is carried out using the same procedure described in example 1. 82 mg of a white solid are obtained. m.p. 65°-67° C. IR (KBr): 1595 (νC--C), 1237 cm-1 (νC--O--C); 1H-NMR (CDCl3): δ 7.5-7.1 (5H,m), 4.8-4.4 (1H,m), 4.7 (2H,s), 3.3-2.5 (2H,m), 2.2 (6H,s), 2.1 (3H,s), 1.9-1.5 (2H,m), 1.0-(3H,t).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22]Cl>CCO>[ClH:19].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Fc1cccc(Cl)c1CCl
Solvent: CCO
Product: Cl
Product: Fc1cccc(Cl)c1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 2-chloro-6-fluorobenzyl chloride (0.204 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 174 mg of the product 231. 1H NMR (DMSO-d6) δ 11.40 (s, 2 H), 7.70-7.30 (m, 3 H), 7.25-6.90 (m, 10 H), 5.88 (s, 2 H), 4.90 (s, 2 H); MS: m/z 397 (M++1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>N1C=CC=CC=1>[C:20]([CH2:19][CH2:18][C:17]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:11](=[O:15])[NH:10][C:9]([NH2:16])=[N:8][C:7]1=2)=[O:23])([OH:22])=[O:21]
Reactant: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Reactant: O=C1CCC(=O)O1
Solvent: c1ccncc1
Product: Nc1nc2c(ncn2COCCOC(=O)CCC(=O)O)c(=O)[nH]1
Yield: 44 %

Procedure:
A mixture of 9-(2-hydroxyethoxymethyl)guanine (0.25 g), succinic anhydride (0.55 g) and pyridine (50 ml) was heated under anhydrous conditions on a steam bath overnight. The solvent was evaporated under reduced pressure at <40° C., the last trace being removed azeotropically with toluene. The residue was triturated with acetone and the product removed by filtration. Recrystallization from methanol afforded 9-{2-(3-carboxypropionyloxy)ethoxymethyl} guanine, m.p. 203°-207° C. (sinter 190° C.), in 44% yield.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH2:24][CH2:25][OH:26])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([S:22][CH3:23])[CH:20]=2)[O:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1([CH2:24][CH:25]=[O:26])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([S:22][CH3:23])[CH:20]=2)[O:15][CH2:14][CH2:13]1
Reactant: CSc1ccc2c(c1)C(C)(CCO)CCO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc2c(c1)C(C)(CC=O)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
To a chilled (−60° C.) solution of 0.31 mL (3.5 mmol) of oxalyl chloride in 5 μL of methylene chloride was added a solution of 0.5 mL (7 mmol) of DMSO in 2.5 mL of dichloromethane. After 10 minutes, a solution of 0.42 g (1.76 mmol) of 2-(4-methyl-6-methylsulfanylchroman-4-yl)ethanol in 2.5 mL of dichloromethane was added. The mixture stirred for 15 minutes and then 1.5 mL (10.6 mmol) of triethylamine was added. The reaction was warmed at room temperature for 30 minutes and then concentrated in vacuo. The residue was diluted with water and extracted with diethyl ether. The combined organic fractions were washed with four portions of water, once with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.4 g (94%) of (4-methyl-6-methylsulfanylchroman-4-yl)acetaldehyde as an oil.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:14]([CH2:16][NH2:17])[OH:15]>>[OH:15][CH2:14][CH2:16][NH:17][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NCCO
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(O)c1ccc(S(=O)(=O)NCCO)cc1

Procedure:
Procedure H was performed to couple 4-(chlorosulfonyl)benzoic acid with ethanolamine to produce 4-(2-hydroxyethylsulfamoyl)benzoic acid which was purified by reverse phase HPLC.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:13]([CH3:14])[C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)=[C:4]([F:17])[CH:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([C:12]1[N:13]([CH3:14])[C:9]([C:5]2[C:4]([F:17])=[CH:3][C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])=[C:7]([F:8])[CH:6]=2)=[CH:10][CH:11]=1)#[N:16]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1cc(F)c(N)cc1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(C#N)ccc1-c1cc(F)c(NS(C)(=O)=O)cc1F
Reaction time: 16 h
Yield: 76 %

Procedure:
5-(4-amino-2,5-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.15 g, 0.64 mmol) was dissolved in pyridine (2.0 mL). Methanesulfonyl chloride (46 μL, 0.6 mmol) was added and the mixture was stirred for 16 hours, followed by the addition of water. The mixture was diluted with ethyl acetate, washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-50% ethyl acetate in hexane) to afford 0.142 g of N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluorophenyl]-methane-sulfonamide.
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH3:17])[C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>CN(C=O)C.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>[Cl:16][C:14]1[CH:13]=[C:12]([CH3:17])[C:8]2[NH:9][C:10](=[O:11])[C:4]3[CH:3]=[C:2]([CH2:24][CH:23]=[CH2:22])[CH:21]=[N:20][C:5]=3[N:6]([CH2:18][CH3:19])[C:7]=2[N:15]=1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCN1c2ncc(Br)cc2C(=O)Nc2c(C)cc(Cl)nc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cnc2c(c1)C(=O)Nc1c(C)cc(Cl)nc1N2CC
Temperature: 100 °C
Yield: 71.3 %

Procedure:
A solution of 8-bromo-2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (12.6 g, 34.3 mmol) in DMF (25-0 mL) was degassed under reduced pressure for 20 min. Pd(PPh3)4 (775 mg, 0.7 mmol) was then added followed by allyltributyltin (12.5 mL, 41.1 mmol). After degassing under reduced pressure for 10 min, the mixture was heated to 100° C. for 7 h. The mixture was then concentrated under reduced pressure. The residue was purified by flash chromatography (hexane:EtOAc, 19:1) to give the title compound (8.04 g, 71% yield) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ccccc1I
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.6 %

Procedure:
A mixture of 2-iodoaniline (1.100 g, 5.00 mmol), 1-Boc-4-piperidone (1.500 g, 7.50 mmol)), acetic acid (1.0 mL, 17.5 mmol) and sodium triacetoxy borohydride (2.420 g, 11 mmol) in 1,2-dichloroethane (30 mL) was stirred at ambient temperature for 2 days. The reaction was quenched with water, and the organic phase was separated. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 4-(2-Iodophenylamino)piperidine-1-carboxylic acid tert-butyl ester (1.560 g, 50%). 1H NMR (300 MHz, CDCl3) δ 7.63 (dd, J=1.5 and 7.8 Hz, 1H), 7.20-7.14 (m, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.41 (dt, J=1.5 and 7.8 Hz, 1H), 3.99-3.95 (m, 2H), 3.48-3.43 (m, 1H), 3.03-2.94 (m, 2H), 2.02-1.97 (m, 2H), 1.52-1.36 (m, 11H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20]CC)=[CH2:19])CCC.[Sn].[Br:32]N1C(=O)CCC1=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Br:32][CH2:20][C:18]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2)=[O:19]
Reactant: O=C1OCCc2cc(Br)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCC(=O)N1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Sn]
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc2c(c1)CCOC2=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
6-Bromo-3,4-dihydro-1H-isochromen-1-one (6.90 g, 30.4 mmol), tributyl(1-ethoxyethenyl)stannane (10.8 mL, 31.9 mmol, 1.05 equiv), and PdCl2(PPh3)2(1.07 g, 1.52 mmol, 0.05 equiv) were weighed into a 250 mL round bottom flask. To this was added dioxane (70 mL) and the resulting mixture stirred at 80° C. for 4 h. The reaction was not complete by HPLC, therefore another 0.1 equiv of tin reagent was added. After 30 min 6-bromo-3,4-dihydro-1H-isochromen-1-one had been fully consumed as indicated by HPLC. The reaction mixture was cooled to 0° C. and 35 mL THF followed by 14 mL H2O were added. To this was introduced solid N-bromosuccinimide (5.68 g, 31.9 mmol, 1.05 equiv), added in portions over 5 min. After stirring for 30 min there was still evidence of remaining enol ether, therefore NBS was added in small portions (˜300 additional mg added) until it was consumed as evidenced by HPLC. Water was then added and the mixture extracted with EtOAc. The aqueous layer was extracted 2 additional times with EtOAc, the combined organics dried with MgSO4, filtered and concentrated in vacuo. This was transferred with EtOAc to a 100 mL round bottom flask, the resulting solution concentrated to ˜25 mL total volume, at which point hexane (50 mL) was added dropwise. When complete the heterogeneous mixture was stirred for 30 min, then cooled to 0° C. and stirred for 10 min, then filtered and washed twice with hexanes. The desired product was dried under a nitrogen bag, then purified by flash chromatography (12 to 100% EtOAc/Hex) to provide the title compound.
Reaction SMILES: [C:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH2:36][CH3:37])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.Br[C:43]1[CH:44]=[N:45][CH:46]=[N:47][CH:48]=1>>[ClH:27].[ClH:27].[CH2:36]([O:35][C:34]1[CH:33]=[CH:32][C:31]([C:43]2[CH:44]=[N:45][CH:46]=[N:47][CH:48]=2)=[CH:30][C:29]=1[CH2:28][N:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][CH3:1])[CH2:14][CH2:13]1)[C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[Cl:27])=[O:17])[CH3:37]
Reactant: Brc1cncnc1
Reactant: CCOc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: CCOc1ccc(-c2cncnc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(NC)CC1
Product: Cl

Procedure:
The title compound is prepared from boronic acid 12 (25 mg, 42 μmol) and 5-bromopyrimidine (5.5 mg, 35 μmol) in accordance with Method L2.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][C:3]=2[O:2]1.C(N([CH:18]([CH3:20])[CH3:19])CC)(C)C.C[N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:11]1[C:10]2[CH:9]=[CH:8][C:5](/[CH:6]=[CH:7]/[C:4]3[CH:3]=[CH:10][CH:9]=[C:19]4[C:18]=3[CH:20]=[C:25]([C:26]#[N:22])[CH:24]=[CH:23]4)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C=Cc1ccc2c(c1)OCO2
Reactant: CN1CCCC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: N#Cc1ccc2cccc(/C=C/c3ccc4c(c3)OCO4)c2c1
Temperature: 25 °C

Procedure:
Example 53B (75 mg, 0.243 mmol), PdCl2(dppf) (20 mg, 0.024 mmol), 3,4-methylenedioxystyrene (43 mg, 0.291 mmol) and diisopropylethylamine (0.170 mL, 0.97 mmol) in N-methylpyrrolidinone (2 mL) were stirred at 90° C. for 18 h, cooled to room temperature and chromatographed on silica gel with 20% ethyl acetate/hexanes to provide 46 mg of the title compound.
Reaction SMILES: C(S)[C@H](N)C(O)=O.Cl.C[O:10][CH2:11][CH2:12][O:13][C:14](=[O:19])[C@H:15]([CH2:17][SH:18])[NH2:16].Cl>>[OH:10][CH2:11][CH2:12][O:13][C:14](=[O:19])[C@H:15]([CH2:17][SH:18])[NH2:16]
Reactant: COCCOC(=O)[C@@H](N)CS
Agent: Cl
Agent: N[C@@H](CS)C(=O)O
Product: N[C@@H](CS)C(=O)OCCO

Procedure:
The first fraction contains 8.0 g L-cysteine.HCl while the second fraction contains 1.0 g L-cysteine-(2-methoxyethyl)-ester.HCl which is contaminated with a slight amount of L-cysteine.HCl.