Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:29])=[O:28])[C:24]1=[O:31])=[O:21])(OCC1C=CC=CC=1)=O.[Na+:32].C(O)(=O)C>CO.[H][H].[Pd]>[NH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:28])=[O:29])[C:24]1=[O:31])=[O:21].[Na+:32]
Reactant: [H][H]
Reactant: O=C(Cc1ccccc1CNC(=O)OCc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NCc1ccccc1CC(=O)NC1CN(S(=O)(=O)[O-])C1=O
Yield: 77.9 %

Procedure:
In 35 ml of 30% methanol is dissolved 0.30 g of the above sodium 3-[2-(2-carbobenzoxyaminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate, followed by addition of 0.68 ml of 6% acetic acid and 76 mg of palladium black. The mixture is stirred in hydrogen gas streams at room temperature for 90 minutes. The catalyst is filtered off and the filtrate is purified on an Amberlite XAD-II column. The above procedure provides 0.167 g of sodium 3-[2-(2-aminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate.acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][NH2:16]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[NH:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: COCCCN
Product: COCCCNc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 3-methoxy-propylamine analogously to the preparation of Intermediate 113.1. colorless oil; ES-MS: M−=227.1; HPLC: AtRet=2.97 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[N:14]([CH2:18][CH2:19][CH3:20])[CH:15]=[CH:16][N:17]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-].C(OCC)(=O)C>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[N:14]([CH2:18][CH2:19][CH3:20])[CH:15]=[CH:16][N:17]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: CCCn1ccnc1C(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCn1ccnc1C(=O)Cc1ccc(N)cc1
Yield: 80.8 %

Procedure:
An aqueous solution (20 ml) of (2-(4-nitrophenyl)-1-(1-propylimidazol-2-yl)ethanone (1.2 g), reduced iron (1.2 g) and anhydrous calcium chloride (244 mg) in 85% ethanol was stirred for 4 hours under nitrogen atmosphere at 105° C. The mixture was allowed to be at room temperature, ethyl acetate was added to the mixture, the insolubles were filtered off, and water was added to separate the layers. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=0.4:1) to give 2-(4-aminophenyl)-1-(1-propylimidazol-2-yl)ethanone (863 mg) as red oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:10][C:11]1[N:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH3:10][C:11]1[N:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=4)[O:28][N:27]=3)=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1cccnc1N
Reactant: Cc1cccc(OCc2ccc(CC(Cl)=NO)cc2)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(OCc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of 3-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 1-2-3 in anhydrous tetrahydrofuran (5 mL) was added (4-(6-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (222 mg, 0.76 mmol) described in Manufacturing Example 3-1-5 at room temperature. Triethylamine (142 μL, 1.0 mmol) was added dropwise to the reaction solution, and stirred overnight at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3 then 1:1) to obtain the title compound (10.5 mg, 11%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]4[NH2:27])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[N+](C1C=CC([CH:39]2[S:43]/[C:42](=[N:44]\[C:45](=O)[O-:46])/[N:41]([C:48]3[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][C:49]=3[CH:55]([CH3:57])[CH3:56])[C:40]2=[O:58])=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:55]([C:49]1[CH:50]=[CH:51][C:52]([CH3:54])=[CH:53][C:48]=1[N:41]1[C:40](=[O:58])[CH2:39][S:43]/[C:42]/1=[N:44]\[C:45]([NH:27][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:28])[F:29])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:46])([CH3:57])[CH3:56]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Reactant: NC1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NC2CCCCC2c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 5.9 %

Procedure:
To 2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)cyclohexanamine (CB56) (0.200 g, 0.497 mmol) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50) (0.205 g, 0.497 mmol) were dissolved in acetonitrile (10 mL) in a vial. Cesium carbonate (0.162 g, 0.497 mmol) was added, and the reaction was stirred at room temperature for 25 hours. The solution was adsorbed onto silica. Purification by reverse-phase flash column chromatography using 0-100% acetonitrile/water as eluent afforded the title compound as a red oil (0.020 g, 6%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:18][CH:17]=[N:16][C:15]=1[CH3:19].[CH3:20][N:21]=[C:22]=[S:23]>O>[CH3:20][NH:21][C:22]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:18][CH:17]=[N:16][C:15]=1[CH3:19])=[S:23]
Reactant: CN=C=S
Reactant: Cc1ncsc1CSCCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=S)NCCSCc1scnc1C
Temperature: 25 °C

Procedure:
Potassium carbonate (7.75 g.) is added to a solution of 15.6 g. of 5-(2-aminoethyl)thiomethyl-4-methylthiazole dihydrochloride in 120 ml. of water. The solution is maintained at ambient temperature for 15 minutes and 5.15 g. of methyl isothiocyanate is added. After refluxing for 1.5 hours, the solution is cooled and the product is collected by filtration to give N-methyl-N'-[2-(4-methyl-5-thiazolylmethylthio)ethyl]-thiourea.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[Br:13][C:9]1[CH:8]=[C:7]([C:17]2[CH2:18][CH2:19][O:14][CH2:15][CH:16]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCOCC1
Reactant: Brc1cccc(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Brc1cccc(C2=CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
n-Butyllithium (2.64 M, 37.9 mL) was added dropwise to a solution of 1,3-dibromobenzene (23.5 g) in tetrahydrofuran (469 mL) at −78° C. The mixture was stirred at the same temperature for 30 minutes, and then tetrahydro-4H-pyran-4-one (10.0 g) was added dropwise. The mixture was stirred at the same temperature for 30 minutes and then warmed to room temperature. After stirring at room temperature for four hours, an ammonium chloride solution was added to the reaction mixture to terminate the reaction. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in toluene (400 mL). p-Toluenesulfonic acid monohydrate (2 g) was added and the mixture was stirred with heating under reflux for two hours. The reaction mixture was cooled to room temperature and purified by NH-silica gel column chromatography to obtain the title compound (21.4 g).
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12](N)=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N([O-])=[O:23].[Na+].O>C(O)(=O)C>[CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12]([OH:23])=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2oc3cc(C#N)c(N)nc3c(=O)c2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc2oc3cc(C#N)c(O)nc3c(=O)c2c1
Temperature: 70 °C

Procedure:
To a solution of 0.5 g of 7-isopropyl-2-amino-3-cyano-1-azaxanthone in 80 ml of acetic acid was added gradually 1.0 g of sodium nitrite at 70° C. After one hour period, 3 ml of water was added to the mixture which was heated at 70° C. for a further one hour. The solvent was distilled off under reduced pressure and then, to the residue, water was added. The yellow precipitate was collected by filtration, rinsed with water and recrystallized from ethanol to give 7-isopropyl-2-hydroxy-3-cyano-1-azaxanthone as yellow crystals, m.p.>300° C.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]1([CH2:13][CH2:14][CH2:15][Br:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH:1]1([C:10]2[CH:11]=[CH:12][C:7]([CH2:13][CH2:14][CH2:15][Br:16])=[CH:8][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCc1ccccc1
Reactant: C1=CCCCC1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: BrCCCc1ccc(C2CCCCC2)cc1
Reaction time: 14 h

Procedure:
17 parts by weight of cyclohexene are added dropwise at +10° C. to a mixture of 40 parts by weight of 3-phenylpropyl bromide and 20 parts by weight of 96% strength sulfuric acid. Stirring is continued for 14 hours at room temperature. The crude product is dissolved in CHCl3 and thhe solution is thoroughly washed with ice water, dried over Na2CO3 and distilled. 35 parts by weight of 3-(4-cyclohexylphenyl)-propyl bromide are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2c(Cl)cccc2s1
Product: Clc1cccc2sc(CCC#Cc3ccccn3)nc12
Yield: 14.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (166 mg, 1.05 mmol) and 2-but-3-ynyl-4-chloro-benzo[d]thiazole (233 mg, 1.05 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 46 mg (0.15 mmol, 14%) of 4-chloro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C(O)C>[N:11]1([C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1nccc2sccc12
Solvent: CCO
Product: c1cc2sccc2c(N2CCNCC2)n1
Yield: 56.1 %

Procedure:
A mixture of 4-chlorothieno[3,2-c]pyridine (22.7 g, 0.13 mole) and piperazine (57.7 g, 0.67 mole) were heated in a bomb with a minimum amount of ethanol (50 mL) at 120° for 24 hours. The reaction was cooled, partitioned between dichloromethane and water, and the organic layer was isolated, dried (MgSO4), filtered, and concentrated in vacuo to an oil. Flash chromatography (methylene chloride-10% methanol-1% ammonium hydroxide) of this material gave 16 g (54%) of a golden oil. Treatment of an ethanol solution of the oil with ethanolic HCl followed by recrystallization from ethanol gave the hydrochloride salt as off-white crystals, m.p. 275°-283°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.BrC[CH2:24][Cl:25]>>[Cl:25][CH2:24][CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:21]
Reactant: ClCCBr
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Product: NC(=O)c1ccc(OCCCl)c(C(=O)Nc2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-chloroethane by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[NH:28][C:29]([NH:17][C:15]1[CH:16]=[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:9][CH:8]=2)[N:12]=[CH:13][N:14]=1)=[O:30]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CCN(CC)c1ccc(Nc2cc(N)ncn2)cc1
Product: CCN(CC)c1ccc(Nc2cc(NC(=O)Nc3c(Cl)cccc3Cl)ncn2)cc1

Procedure:
The title compound is prepared analogously as described in Example 105A from N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>COCCOC>[OH:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]2[N:7]([CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[CH:6]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1ccc(CO)cn1
Solvent: COCCOC
Product: CCOC(=O)c1cn2cc(CO)ccc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
To a 100 mL flask under a N2 atmosphere were added DME (35 mL) and the product from Example 9 (0.60 g, 4.8 mmol). After stirring for 20 min, ethyl bromopyruvate (1.03 g, 5.3 mmol) was added and the reaction was allowed to stir at room temperature for 16 h. The resulting precipitate was filtered and washed once with Et2O. The solid was suspended in abs EtOH (35 mL) and heated to reflux for 2 h. The resulting solution was cooled to room temperature and all solvent removed in vacuo. Aqueous K2CO3 was added to the residue, and the product was extracted with CH2Cl2. The extracts were dried (MgSO4) and stripped to leave 0.793 g (75%) of title product.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:23]12[CH2:30][NH:29][CH2:28][C:27]=1[CH2:26][NH:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:25]4[CH2:26][C:27]5[CH2:28][NH:29][CH2:30][C:23]=5[CH2:24]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
0.4 g of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 0.8 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 0.8 ml of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) were suspended in 30 ml of acetonitrile and the suspension was refluxed in 100° C. oil bath for 8 hours. The reaction mixture was kept overnight at room temperature. The produced precipitate was filtered and washed with methanol. 0.35 g of the title compound was obtained (yield 67%)
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:12]N1C(=O)CCC1=O.O>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[C:10]([Cl:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(Br)cnc2[nH]ccc12
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Br)cnc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.9 %

Procedure:
The compound obtained in Step 3 of Example 36 (323 mg) was dissolved in tetrahydrofuran (6 ml). N-Chlorosuccinimide (225 mg) was added and the mixture was stirred at room temperature for three days. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (364 mg).
Reaction SMILES: I[CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][CH2:8][C:9]1[S:13][C:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N:11][N:10]=1.[H-].[Na+]>O1CCCC1>[C:17]([O:16][C:15]([N:14]=[C:12]1[N:11]([CH2:2][C:3]([OH:5])=[O:4])[N:10]=[C:9]([CH2:8][O:7][CH3:6])[S:13]1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: COCc1nnc(NC(=O)OC(C)(C)C)s1
Reactant: O=C(O)CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nn(CC(=O)O)c(=NC(=O)OC(C)(C)C)s1
Temperature: 60 °C
Yield: 90 %

Procedure:
Iodoacetic acid (409.3 g, 2.2 mol, 1.5 eq) is added in one portion to a solution of tert-butyl [5-(methoxymethyl)-1,3,4-thiadiazol-2-yl]carbamate a13 (360 g, 1.47 mol, 1 eq) in tetrahydrofurane (3 l) at room temperature. Sodium hydride (52.8 g, 2.2 mol, 1.5 eq) is then added portionwise, in 30 minutes, at room temperature. The reaction mixture is heated at 60° C. overnight, and the solvent is evaporated under reduced pressure. Water is added to the residue, the solution is acidified to pH=2 with aqueous 6N HCl, then extracted with CH2Cl2. The organic layer is washed with 10% aqueous sodium thiosulfate and evaporated to dryness to afford 455.7 g of {2-[(tert-butoxy-carbonyl)imino]-5-(methoxymethyl)-1,3,4-thiadiazol-3(2H)-yl}acetic acid a14 which is used directly in the next step without any further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C@@H:10]2[CH2:15][O:14][C:13]3=[N:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][N:12]3[CH2:11]2)=[N:6][CH:7]=1.[C:22]([Si](C)(C)C)#[CH:23]>CN(C=O)C.CCN(CC)CC.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.[Cu](I)I>[C:22]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C@@H:10]2[CH2:15][O:14][C:13]3=[N:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][N:12]3[CH2:11]2)=[N:6][CH:7]=1)#[CH:23]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Br)cn1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccc(CO[C@@H]2COc3nc([N+](=O)[O-])cn3C2)nc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
A mixture of bromide 59 (see Example 21) (0.310 g, 0.873 mmol), PdCl2(PPh3)2 (33 mg, 0.047 mmol) and copper iodide (18 mg, 0.095 mmol) in DMF (4 mL) and Et3N (4 mL) was purged with N2. Ethynyltrimethylsilane (0.61 mL, 4.3 mmol) was added and the mixture was stirred in a sealed tube at 50° C. for 18 h, and then partitioned between EtOAc and water. The residue was dissolved in THF (20 mL), cooled to 0° C. and treated with TBAF (1M in THF, 1.8 mL), and then the solution was stirred for 2 h. Removal of the solvent gave a residue which was partitioned between EtOAc and water. Column chromatography of the organic portion on silica gel using gradient elution (0-5% MeOH:EtOAc) gave (6S)-6-[(5-ethynyl-2-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (97) (0.178 g, 68%) as a tan solid: mp 135-136° C.; 1H NMR [(CD3)2SO] δ 8.61 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.90 (dd, J=8.0, 2.2 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 4.78 (d, J=13.8 Hz, 1H), 4.74 (d, J=13.8 Hz, 1H), 4.69 (dt, J=12.0, 2.6 Hz, 1H), 4.49 (d, J=12.0 Hz, 1H), 4.40 (s, 1H), 4.30-4.35 (m, 2H), 4.25 (dd, J=13.7, 3.5 Hz, 1H). Anal. (C14H12N4O4) C, H, N.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[N:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[N:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=3)[N:4]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:37][CH:36]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a 5 ml microwave vial equipped with a stir bar was added ethyl 3-bromo-1-trityl-1H-indazole-5-carboxylate (1095.3 mg, 2.142 mmol), pyridine-4-boronic acid pinacol ester (679 mg, 3.21 mmol), sodium carbonate (2142 μl, 4.28 mmol), dioxane (1.07E+04 μl), and PalladiumTetrakis (247 mg, 0.214 mmol). The vial was purged with nitrogen, and was then sealed and heated to 80° C. for 24 h. LCMS taken after 24 hours indicates formation of the desired product. The crude reaction mixture was filtered through a column pre-packed with celite. The combined organics were concentrated under reduced pressure and the material was dry loaded onto a 100 g column. A column was run from 100% hexanes to 100% ethyl acetate. The desired product eluted; fractions were collected and concentrated in vacuo
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2SC)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([NH:21][C:22]([NH2:24])=[NH:23])([CH3:20])[CH3:19]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[O:15])[N:11]=[C:10]2[NH:24][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[NH:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)NC(=N)N
Reactant: CSC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: CC(C)NC(=N)NC1=NC(=O)C(=O)N1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-(3,4-dichlorophenyl)-2-methylsulfanyl-1H-imidazole-4,5-dione (15, 1.89 g, 6.54 mmol) was dissolved in 10 ml of dried DMF and cooled with an ice bath to 0° C. To the solution was added dropwise 40 ml of DMF solution containing guanidine 18 (1.369 g, 13.554 mmol). The solution was stirred at room temperature for 2 hours after addition and then further stirred at 50° C. for 24 hours. The solvent DMF was dried under vacuum and the crude product was suspended in 30 ml of chloroform. The yellow solid was collected, washed sequentially with 3×20 ml of CHCl3 and 10 ml of methanol to afford compound 4 as a white color powder (1.588 g, 6.54 mmol, 71%), mp 245° C.: NMR indicates that the compound exists in two tautomeric forms in the CDCl3 solution. 1H NMR (600 MHz, DMSO-d6) (Major tautomer): δ 8.74–8.69 (m, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.6 and 2.2 Hz), 3.73 (m, 1H), 1.14 (d, J=6.4 Hz, 6H); 13C NMR: δ 168.60, 162.45, 161.15, 161.09, 134.01, 131.84, 131.48, 131.20, 130.29, 128.86. IR: 1757, 1722, 1645, 1595, 1551, 1535, 1480, 1304, 997, 754 cm−1; MS (m/z): 342 (M+), 271, 229, 187, 127. Anal. (C13H13Cl2N5O2.0.25H2O) C, H, Cl, N.