Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])[CH2:31][CH2:30]3)[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCC(N2N=C(c3ccc(OC)c(OC)c3)[C@H]3CC=CC[C@H]3C2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 20 mmol of 2-chloroethylsulfonylchloride in 20 ml of dichloromethane is added to a solution of 15 mmol of compound 5c and 25 ml of diisopropylethylamine in 50 ml of dichloromethane. The resulting mixture is stirred at RT for 18 h, after which it is washed first with diluted hydrochloric acid and then with a saturated solution of sodium bicarbonate. After drying over magnesium sulfate and evaporating the solvent, the compound is crystallised from diethyl ether. M. p. 89-90° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[O:16]1[CH2:19][C:18](=[O:20])[CH2:17]1>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2([OH:20])[CH2:19][O:16][CH2:17]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C1COC1
Reactant: COc1cc(I)ccc1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C2(O)COC2)ccc1Br
Reaction time: 0.17 h

Procedure:
A solution of 1-bromo-4-iodo-2-methoxybenzene (Combi-Blocks, 3.00 g, 9.59 mmol) in 40 mL ether was cooled to −78° C. and was treated with n-butyllithium (4.22 ml, 10.55 mmol). After stirring for 10 minutes, the reaction mixture was quenched with 3-oxetanone (0.967 ml, 13.42 mmol), and the cooling bath was removed. After stirring for an additional hour, LC/MS showed mostly product, so the reaction mixture was washed with 1N citric acid solution, the organics dried over MgSO4 and concentrated. This material was carried on to step two without purification. (M+H)+=240.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(=O)(O)(O)O>O>[C:10]1(/[CH:9]=[CH:8]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC(Cc1ccccc1)c1ccccc1Br
Agent: O=P(O)(O)O
Solvent: O
Product: Brc1ccccc1/C=C/c1ccccc1
Temperature: 170 °C
Yield: 86.5 %

Procedure:
A stirring mixture of 1-(2-bromophenyl)-2-phenyl-ethan-1-ol (15.50 g) and orthophosphoric acid (150 ml) was heated at 170° C. for 1 hour and then poured into iced water and extracted with ether. The extracts were washed with water, dried and concentrated to give the crude product as an orange oil (14.29 g). Evaporative distillation (0.3 torr; oven temperature 140° C.) gave E-1-phenyl-2(2bromophenyl)ethylene (12.53 g), 86% yield) as a pale yellow oil with a purity of 97% by GC.
Reaction SMILES: C1C=CC=CC=1.[C:7]([C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[CH:15][C:16]=1[Cl:17])([CH3:10])([CH3:9])[CH3:8].[Cl:19][C:20](OC(Cl)(Cl)Cl)=[O:21].C(N(CC)CC)C>CCCCCC>[Cl:19][C:20]([O:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([C:7]([CH3:10])([CH3:8])[CH3:9])[CH:12]=1)=[O:21]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)ccc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(OC(=O)Cl)ccc1Cl
Yield: 135.7 %

Procedure:
Into 50 ml of benzene were dissolved 9.2 g of 3-tert-butyl-4-chlorophenol and 5.5 g of trichloromethyl chloroformate, and a solution obtained by dissolving 5.8 g of triethylamine into 20 ml of benzene was added dropwise thereto with stirring and cooling by ice. After completion of this dropwise addition, the mixture was subjected to stirring for 12 hours at room temperature. To the reaction mixture were added 70 ml of hexane, and precipitated crystal was separated by filtration. The filtrate was washed with water and a saturated aqueous solution of sodium chloride in this order, and was dried over anhydrous calcium chloride. Thereafter, solvent was distilled off. The residue was distilled under reduced pressure to give 9.32 g of 3-tert-butyl-4-chlorophenyl chloroformate having boiling point of 105°-108° C./1 mmHg, of which properties are as follows.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[C:12](=[O:20])[N:13]([CH3:19])[N:14]=[CH:15][C:16]=2[O:17]C)[CH:3]=1.N1CCOCC1>O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH:11]2[C:16](=[O:17])[CH:15]=[N:14][N:13]([CH3:19])[C:12]2=[O:20])[CH:3]=1
Reactant: COc1cnn(C)c(=O)c1-n1cc(Cl)c2ccccc21
Solvent: O
Solvent: C1COCCN1
Product: CN1N=CC(=O)C(n2cc(Cl)c3ccccc32)C1=O
Temperature: 140 °C
Yield: 95 %

Procedure:
A mixture of 4-(3-Chloro-indol-1-yl)-5-methoxy-2-methyl-2H-pyridazin-3-one (1.70 g, 5.87 mmol) and morpholine (8 ml) is heated to 140° C. under microwave irradiation for 10 min. The mixture is allowed to cool then evaporated under reduced pressure to remove most of the morpholine. The residue is stirred with 1:1 v/v glacial AcOH:DCM (100 ml) to give a free-flowing semi-solid. Volatiles are removed in-vacuo and the solid obtained slurried with water. The solid is recovered by filtration under reduced pressure and dried at 1 mBar and 60° C. to give the title compound as a beige solid, 1.54 g, 95% yield. 1H nmr (DMSO-d6) δ (ppm) 7.89 (1H, s), 7.57-7.50 (2H, m), 7.24-7.17 (2H, m), 7.12-7.06 (1H, m), 3.66 (3H, s)
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[N:8][NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:21]>ClC1C=CC=CC=1>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=[N:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(=O)cn[nH]c2c1
Solvent: Clc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2c(Cl)cnnc2c1
Yield: 69.1 %

Procedure:
7-Methyl-1-H-cinnolin-4-one (1.3 g, 8.1 mmol) is treated with about 80 mL of chlorobenzene and heated until the solid dissolves. The resulting solution is cooled and treated with pyridine (0.16 mL, 2 mmol) and POCl3 (1.13 mL, 12.2 mmol). The solution is heated to reflux for 1 h then concentrated to dryness. The residue is chromatographed (20% ethyl acetate/hexane) to yield the title compound as a tan solid (˜1 g, 5.6 mmol). MS m/z (M+=178); 1H NMR (CDCl3, 300 MHz) δ9.3 (s, 1H), 8.35 (s, 1H), 8.1 (d, 1H), 7.7 (d, 1H), 2.68 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][C:16](N)=[C:17]([C:19]([O:21]CC)=[O:20])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N(OC(C)(C)C)=O.[Cl-].[NH4+]>[Cu](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C2CCCN(C(=O)OC(C)(C)C)C2)sc1N
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(C(=O)O)cs2)C1
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
3-(5-Amino-4-ethoxycarbonyl-thiophen-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.45 g, 4.1 mmol) was added to a suspension of t-butyl nitrite (6.1 mmol) and copper (II) chloride (4.1 mmol) in IMS (100 mL). The reaction was stirred for 30 minutes. Saturated aqueous ammonium chloride (7 mL) was added and the mixture stirred overnight. The solvent was removed under vacuum and product partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate, filtered and the solvent removed. The residue was purified by column chromatography on silica, eluting with 0%-40% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound as a pale yellow oil (1.08 g). LCMS m/z 362.20 [M+Na]+ RT=4.30 min (Analytical Method 4).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1)[CH3:10]>CN(C=O)C>[CH2:1]([N:15]1[CH2:14][CH2:13][NH:12][CH:11]([CH2:9][CH3:10])[CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCC1CNCCN1
Solvent: CN(C)C=O
Product: CCC1CN(Cc2ccccc2)CCN1
Reaction time: 1 h
Yield: 70.3 %

Procedure:
Benzyl bromide (38.7 g, 0.22 mol) was added in portions to a chilled (˜0° C.) solution of 2-ethylpiperazine (25 g, 0.22 mol) in DMF (150 mL) with such a rate that the temperature did not exceed 20° C. The mixture was stirred for 1 h, the solvent was evaporated and the residue was partitioned between CHCl3/0.5 M aqueous HCl. The aqueous phase was made alkaline (11 M NaOH) and extracted three times with CHCl3. The combined organic phases were dried (MgSO4) and concentrated. The resulting oil was purified by column chromatography on silica using CHCl3, followed by CHCl3/MeOH/NH4OH (95:5:0.3) as eluents to give 31.6 g (70%) of the title compound as a yellowish oil. Anal. (C13H20N2) H, N; C: calcd, 76.42; found, 75.85. *Described in WO 00/76984.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH2:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][S:10]([CH3:9])(=[O:12])=[O:11]
Reactant: CC1CCCC1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1CCCC1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a stirred solution of 2-methylcyclopentanamine hydrochloride (0.100 g, 0.7 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown solid (0.100 g, 84%). The material was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[O:19]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:27][CH:28]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(Oc2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 4-phenoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 404.15 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[CH2:38][OH:39]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][C@H:33]5[CH2:38][OH:39])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:31])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC[C@@H]1COCCN1
Product: O=C1N=C(N2CCOC[C@H]2CO)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3(R)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (3R)-Morpholin-3-yl-methanol following General Procedure C.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[N:21]1[N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]2=[C:23]([C:30](O)=[O:31])[CH:22]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:30]([C:23]1[CH:22]=[N:21][N:25]2[CH:26]=[CH:27][CH:28]=[N:29][C:24]=12)=[O:31]
Reactant: O=C(O)c1cnn2cccnc12
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (80.0 mg, 0.259 mmol) in DMF (5 ml) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (42.3 mg, 0.259 mmol), HOBT.H2O (39.7 mg, 0.259 mmol) and HBTU (98.0 mg, 0.259 mmol). Finally DIPEA (0.136 ml, 0.778 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. DMF was evaporated in vacuo then 5 ml of DCM added and washed with saturated aq. NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were collected and concentrated in vacuo to give the title compound as a white solid (105 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:11])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23](=O)[CH3:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:9][NH:10][CH:23]([CH3:24])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COc1ccc(CC(C)=O)cc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1OC

Procedure:
In accordance with the above preferred reaction scheme 2-(3-chlorophenyl)-2-hydroxyethylamine 1, and 3,4-dimethoxyphenylacetone 2 are reacted with sodium cyanoborohydride in methanol, giving 3-chloroalpha-(((2-(3,4-dimethoxyphenyl)-1-methylethyl)amino)methyl) benzenemethanol 3 which is reacted with carbonyl diimidazole and triethylamine in tetrahydrofuran, followed by separation of isomers, giving cyclized derivative 4 which is reacted with boron tribromide in dichloromethane, giving (R*,R*)-(±)-5-(3-chlorophenyl)-3-(2-(3,4-dihydroxy phenyl)-1-methylethyl)2-oxazolidinone 5. Compound 5 is then reacted with diethyl dibromomalonate and anhydrous potassium carbonate in acetone, giving (R*,R*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester 6 which is then reacted first with sodium hydroxide in ethanol and then with hydrogen chloride gas in methanol, giving the product (R*,R*)-(±) 5-(2-((2-(3-chlorophenyl) 2-hydroxyethyl)-amino)propyl-1,3-benzodioxole-2, 2-dicarboxylic acid, dimethyl ester 7.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])=[CH:10][C:4]=2[NH:3]1.CCO.[OH-].[Na+].CC(O)=O>O>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:17])[C:12]([OH:14])=[O:13])=[CH:10][C:4]=2[NH:3]1
Reactant: CCOC(=O)C(C)c1ccc2[nH]c(=O)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 40 °C
Reaction time: 10 h
Yield: 63.6 %

Procedure:
To the flask of Ethyl 2-(2,3-dihydro-2-oxo-1H-benzo[d]imidazol-5-yl)propanoate (175 mg, 0.747 mmol) was added 90% aq. EtOH (5 mL) at room temperature, and additionally added NaOH (70 mg). The reaction mixture was stirred for 10 hrs at 40° C. then cooled to room temperature. The mixture was diluted with H2O (25 mL) and acidified with AcOH (4 mL, pH=4) then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using CH2Cl2:MeOH (10:1) as eluant. Pale brown solid, yield: 63.6%
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([N:10]=[C:11]=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[C:26]=2[N+:32]([O-:34])=[O:33])=[CH:22][C:21]=1[F:37]>>[NH2:31][C:27]1[C:26]([N+:32]([O-:34])=[O:33])=[C:25]([O:24][C:23]2[CH:35]=[CH:36][C:20]([NH:19][C:11]([NH:10][C:8]3[N:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:9]=3)=[O:12])=[C:21]([F:37])[CH:22]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1F
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(N)c3[N+](=O)[O-])cc2F)n(-c2ccccc2)n1

Procedure:
Using Method F3 with -tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole (15 mL, 4.05 mmol) and 4-(4-amino-3-fluorophenoxy)-3-nitropyridin-2-amine (893 mg, 3.38 mmol) the title compound was obtained in quantitative yield (1.71 g) as a yellow solid after column chromatography with 5% to 50% EtOAc in CH2Cl2.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][O:11][CH2:10][C:9]=2[S:8][C:7]=1[NH2:15])=O)C.[CH:16]([NH2:18])=O>>[N:15]1[C:7]2[S:8][C:9]3[CH2:10][O:11][CH2:12][CH2:13][C:14]=3[C:6]=2[C:4](=[O:3])[NH:18][CH:16]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2c1CCOC2
Product: O=c1[nH]cnc2sc3c(c12)CCOC3
Temperature: 25 °C
Yield: 42 %

Procedure:
2-Amino-4,5-dihydro-7H-thieno[2,3-c]pyran-3-carboxylic acid ethyl ester (26 g, 0.114 mol) was dissolved in formamide (200 ml) and the resulting mixture was heated at reflux temperature for 1.5 h. After cooling to room temperature the precipitate was filtered off, washed with water (2×80 ml) and dried in vacuo at 50° C. for 18 h which afforded 10.0 g (42%) of 5,6-dihydro-8H-pyrano[4′,3′:4,5]thieno[2,3-d]pyrimidin-4-one as a solid.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].F[B-](F)(F)F.[C:10]([C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=1[N+]#N)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Cu](SC#N)SC#N.O>[C:10]([C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=1[S:1][C:2]#[N:3])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#C[S-]
Reactant: N#[N+]c1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: N#CS[Cu]SC#N
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: O
Product: N#CSc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Reaction time: 20 h

Procedure:
To a mixture of potassium thiocyanate (42 g), copper thiocyanate (4s g) and water (400 ml), 2-benzoyl-5-carboxy3-nitrobenzenediazonium tetrafluoroborate (prepared as described in Example 17, step A; 28 g) is added in portions while stirring at 45°-50° C. After the addition is completed, the mixture is stirred at about 50° C. for a further 4 hours and thereafter at room temperature for about 20 hours. The resulting precipitate is collected by filtration, washed with water and dried. The dried solids are then extracted with boiling ethanol (three portions of 250 ml, 100 ml, and 100 ml, respectively) and filtered hot. The combined filtrates are evaporated in vacuo and the residue is crystallized by trituration with 50% aqueous ethanol (100 ml). The material is collected by filtration, washed with cold 50% ethanol and dried. After recrystallization from aqueous ethanol, 4-benzoyl-5-nitro-3-thiocyanobenzoic acid is obtained with a melting point of 183.5°-184.5° C.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](=[O:18])([O-])[O-:16].[K+].[K+]>C(O)C>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:14]2[CH2:13][CH2:8][CH:9]2[C:15]([O:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(OCc1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Yield: 52 %

Procedure:
An alternative to the procedures of Examples 1b-1c, (R)-1-t-butyloxycarbonyl-2-azetidinemethanol was prepared from γ-butyrolactone according to the procedure of Rodebaugh, R. M. and Cromwell, N. H., (J. Heterocyclic Chem., 1969, 435). In this literature procedure, γ-butyrolactone was treated with bromine and catalytic phosphorus tribromide, then subsequently with benzyl alcohol and gaseous hydrogen chloride to afford benzyl α,γ-dibromobutyrate in 62% yield. This dibromide in ethanol was treated with one equivalent of benzhydrylamine and potassium carbonate at reflux for about 16 hours to afford benzyl N-diphenylmethylazetidine-2-carboxylate in 52% yield. Hydrogenolysis in MeOH over Pd(OH)2 afforded racemic azetidine-2-carboxylic acid in 62% yield. Following the procedure of Rodebaugh, R. M. and Cromwell, N. H., (J. Heterocyclic Chem., 1969, 993), racemic azetidine-2-carboxylic acid was converted to the N-Cbz derivative by treatment with benzyl chloroformate in aqueous NaOH at 0-5° C. Following isolation in quantitative yield, the Cbz derivative in methanol was treated with one equivalent of L-tyrosine hydrazide to precipitate the tyrosine hydrazide salt of (R)-azetidine-2-carboxylic acid in 77-87% yield. (R)-1-Cbz-azetidine-2-carboxylic acid was liberated from the salt by normal extractive procedures. Hydrogenolysis of the free acid by treatment of a methanol solution with hydrogen gas at 4 atm in the presence of 10% Pd/C for 19 h afforded (R)-azetidine-2-carboxylic acid, which was isolated in 88% yield by trituration with methanol. This product was treated with di-tert-butyl dicarbonate and N-methylmorpholine in dioxane/H2O (1:1) to afford (R)-1-Boc-azetidine-2-carboxylic acid in quantitative yield. Treatment of a THF solution of (R)-1-Boc-azetidine-2-carboxylic acid with borane-methyl sulfide complex for 16 h at ambient temperature afforded the title compound in 92% yield.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[N:8][CH:9]=1
Reactant: c1nc[nH]n1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Brc1ccc(-n2cncn2)nc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 13.2 %

Procedure:
A mixture of 1,2,4-triazole (1.17 g, 16.9 mmol), 2,5-dibromopyridine (2 g, 8.4 mmol) and K2CO3 (1.2 g, 8.7 mmol) in NMP (20 mL) was heated at 100° C. with stirring for 5 hours. After cooling, the reaction mixture was poured into water (100 mL) and solid was collected by filtration and further purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) provided the title compound (250 mg, 13%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:16])[CH:14]=O.COC(OC)N(C)C>CO>[Cl:1][C:2]1[C:7](/[CH:8]=[CH:12]/[N:13]([CH3:16])[CH3:14])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Agent: COC(OC)N(C)C
Solvent: CO
Product: CN(C)/C=C/c1c(Cl)cccc1[N+](=O)[O-]

Procedure:
A 2-liter flask fitted with a 30-cm. vacuum-jacketed Vigreux column, downward condenser, and receiver with a nitrogen inlet was charged with 171.6 g. of 6-chloro-2-nitrotoluene, 500 ml. of dimethylformamide, and 149.0 g. of N,N-dimethylformamide dimethyl acetal and then heated to 140°-156° for 13 hours. The pot temperature was maintained by continuous distillation of the methanol as it was formed.