Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])=[CH:24][C:23]=1F>>[O:34]=[C:29]1[CH2:30][O:31][CH2:32][CH2:33][N:28]1[C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:4]([C:6]2[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]3[S:16][C:17]([Cl:20])=[CH:18][CH:19]=3)=[O:14])[N:7]=2)=[O:5])=[CH:27][CH:26]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1nc(CNC(=O)c2ccc(Cl)s2)no1

Procedure:
In analogy to example 1E 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (example 1D) was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid [4-(3-oxo-morpholin-4-yl)-phenyl]-amide. Light yellow solid. MS 462.0 ([M+H]−)
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]1[CH3:14].[OH-].[Na+].Cl>CO.C1COCC1>[F:15][CH:2]([F:1])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[C:5]1[CH3:14]
Reactant: CCOC(=O)c1cn(CC(F)F)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)cn1CC(F)F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
Ethyl 1-(2,2-difluoroethyl)-2-methyl-1H-imidazole-4-carboxylate (1.375 mmol, 300 mg) was dissolved in methanol (0.5 ml) and THF (4 ml). NaOH 2 M (4.12 mmol, 2.062 ml) was added and the resulting mixture was stirred for 2.5 h at RT. The pH of the mixture was adjusted to about 6 with 5 M HCl and the solvents were evaporated. Ethanol was added and filtered. The filtrate was evaporated. 176 mg of the title compound was obtained. The two isomers formed in the previous reaction were still present. Isomer 1: 1H-NMR (400 MHz, DMSO-d6): δ 2.25 (s, 3H), 4.67-4.80 (m, 2H), 6.09-6.44 (m, 1H), 6.94 (s, 1H). Isomer 2: 1H-NMR (400 MHz, DMSO-d6): δ 2.27 (s, 3H), 4.32-4.44 (m, 2H), 6.17-6.47 (m, 1H), 7.15 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([CH:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:35])[CH2:9]2)=[C:4]([C:36]([F:39])([F:38])[F:37])[CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[S:21][C:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:35])[CH2:9]2)=[C:4]([C:36]([F:38])([F:37])[F:39])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1ccc(C2CCNCC2)s1
Yield: 60.3 %

Procedure:
Prepared according to the synthesis of Example 29EY in Step 4C from (R)-tert-butyl 4-(5-(4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methylpiperazin-1-ylsulfonyl)thiophen-2-yl)piperidine-1-carboxylate (150 mg, 0.253 mmol) in DCM (3 mL) and TFA (1 mL), purified by SiO2 column eluted with EtOAc/MeOH to give the titled compound as a white solid (75 mg, 60%). HRMS: calcd for C21H25F4N3O2S2+H+, 492.13970. found (ESI-FTMS, [M+H]1+), 492.14043.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Cl[CH2:7][CH:8]1[CH2:12][S:11][C:10]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[S:9]1>CN(C=O)C.O>[C:1]([S:3][CH2:7][CH:8]1[CH2:12][S:11][C:10]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)[S:9]1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)CC1CCC2(C1)SCC(CCl)S2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCC2(C1)SCC(CSC(C)=O)S2
Yield: 103.5 %

Procedure:
A mixture of potassium thioacetate (5.4 g, 0.047 mole) and a solution of the product of Example E (4.0 g, 0.013 mole) in DMF (40 ml) was stirred under nitrogen for 2 days at room temperature. The reaction mixture was diluted with water (200 ml) and extracted twice with ethyl acetate. The organic phase was washed with brine and dried (Na2SO4). The drying agent was filtered and the filtrate stripped on the rotary evaporator to give 4.5 g of the titled compound. This material was a single spot on TLC.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][CH2:14][C:15]([NH:17][C:18]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C1COCC1.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:28][C:25]1[CH:26]=[CH:27][C:18]([NH:17][C:15](=[O:16])[CH2:14][O:13][C:12]2[CH:11]=[CH:10][CH:31]=[C:30]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:29]=2)=[C:19]([CH:24]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: OB(O)c1ccoc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COc1cccc(Br)c1
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: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)COc1cccc(-c2ccoc2)c1
Reaction time: 1 h
Yield: 10.4 %

Procedure:
210 mg (10.7 mmol) of 3-furan boronic acid, 500 mg (7.13 mmol) of methyl 2-{[(3-bromophenoxy)acetyl]amino}-5-chlorobenzoate, 144 mg (0.713 mmol) of tetrakis(triphenylphosphine)palladium(0), and 613 mg (10.7 mmol) of cesium carbonate were heated under reflux for 6 hours in THF (5 mL). After the completion of the reaction, ethyl acetate was added thereto, and the mixture was stirred for 1 hour and filtered using a silica gel pad. After the filtrate was condensed, the obtained crude product was separated and purified by silica gel column chromatography. IPE was added to the resulting solids, followed by collection by filtration, washing with IPE, and drying under reduced pressure at 50° C. for 5 hours, thereby giving 286 mg of methyl 5-chloro-2-({[3-(furan-3-yl)phenoxy]acetyl}amino)benzoate (yield: 59%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:25][CH2:22][C:23]#[CH:24])=[O:11])[CH2:7]1
Reactant: C#CCN
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 42 h
Yield: 64.7 %

Procedure:
A stirred mixture of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.02 mole) of 2-propynylamine added dropwise from a needle and syringe. A piece of ice was added and stirring was continued for 42 hr. The solid residue which remained was stirred with 100 ml of water then filtered, yielding 5.3 g of crude product. Recrystallization from ethanol yielded 4.0 g of fine beige crystals, m.p. 145°-147° C. After drying at 100° C. in vacuo, m.p. was 146°-147° C. (64.7%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:16])([C:14]#[CH:15])[C:10]([F:13])([F:12])[F:11].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17](=[O:18])[O:16][C:9]([C:14]#[CH:15])([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: C1CCOC1
Product: C#CC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Temperature: 60 °C

Procedure:
A THF solution of 2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-3-butyn-2-ol (5.0 g, 20.0 mmol in 225 mL THF) was treated with 1,1'-carbonyldiimidazole (13.0 g, 80.0 mmol) and heated in an oil bath at 60° C. for 17 h. The THF was removed in vacuo, the residue dissolved in ethyl acetate then washed with 10% citric acid, sodium bicarbonate, water and brine before drying over sodium sulfate. Following filtration and evaporation in vacuo the crude product was isolated (3.6 g) and recrystallized from ethyl acetate:hexane. The product (+/-) 6-chloro-4-ethynyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one was isolated as a white crystalline solid (3.22 g, 58.4% yield): mp 226°-227° C. 1H-NMR (CDCl3 +trace DMSO): δ 3.16 (s, 1H), 6.98 (d, J=3.3 Hz, 1H), 7.35 (m, 1H), 7.51 (s, 1H), 10.66 (s, 1H).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C(Cl)Cl>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:18]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCCC#Cc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/CCC#Cc1ccccc1
Yield: 83.2 %

Procedure:
5-Phenylpent-4-ynal (3 g) in dry CH2Cl2 (30 ml) was added to a solution of carbethoxymethylenetriphenylphosphorane (10 g) in dry dichloromethane (20 ml), and the mixture was heated at reflux under a nitrogen atmosphere for 5 hours. The solvent was removed under reduced pressure, and the product was purified by chromatography on silica (150 g), eluting with 2:1 hexane:ether to yield ethyl 7-phenylhept-2E-en-6-ynoate (3.6 g).
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[O:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH2:23])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]>C(O)=O>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:28])[C:12]2[O:18][C:17]3[C:19]([Cl:24])=[CH:20][C:21]([NH:23][CH:1]=[O:2])=[CH:22][C:16]=3[CH2:15][S:14](=[O:26])(=[O:25])[C:13]=2[CH:27]=1)=[O:8]
Reactant: O=C[O-]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC=O)cc(Cl)c1O2
Temperature: 0 °C

Procedure:
Sodium formate (7.29 g, 0.108 mol) was added to a suspension of compound of Example 1 (20 g, 0.054 mol) in formic acid (200 mL) and refluxed for 1.5 h. The reaction mixture was cooled and poured into ice water (800 mL). The solid precipitated was filtered, washed with water and dried. The crude product was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 18 g, (83%); mp 258-262° C. (decomposed); 1H NMR (DMSO-d6, 300 MHz): δ 2.64 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 5.25 (s, 2H, CH2, trans minor isomer), 5.33 (s, 2H, CH2, cis major isomer), 7.33 (d, 1H, Ar, trans minor isomer), 7.50 (d, 1H, Ar, trans minor isomer), 7.69 (d, 1H, Ar, cis major isomer), 7.86 (d, 1H, Ar, cis major isomer), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar), 8.30 (s, 1H, CHO, cis major isomer), 8.80 (d, 1H, CHO, trans minor isomer), 10.40 (d, 1H, NH, trans minor isomer), 10.57 (s, 1H, NH, cis major isomer); MS: m/e (ES−) 394 (M−1); analysis: C17H14ClNO6S requires C, 51.54; H, 3.56; N, 3.54; Cl, 8.96; S, 8.10. found: C, 51.96; H, 3.63; N, 3.60; Cl, 9.43; S, 8.50%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)[CH3:2].[CH:14](O)=O>>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[CH:14][NH:12][C:7]=2[CH:6]=1)=[O:13])[CH3:2]
Reactant: O=CO
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Product: CCOC(=O)c1ccc2nc[nH]c2c1
Yield: 70.2 %

Procedure:
40 g of 3,4-diaminobenzoic acid ethyl ester (0.22 mol) and 200 mL formic acid were added to a three-necked bottle. After refluxing for 7 h, the reaction was completed. After concentration under reduced pressure, the ice water was poured into the residual solution. The resulting mixture was adjusted to pH 7 with sodium hydroxide. After sucking filtration, the filtrate was extracted with dichloromethane thrice, dried with anhydrous sodium sulfate, and decolored with active charcoal. Then the solution was concentrated under reduced pressure to get a white solid (29.6 g). Yield: 70.2%. MS: 191 (M+1)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:20](=[O:40])[C:19]=3[C:18]=2[O:41][CH3:42])=[O:16])[CH:10]([CH3:43])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:42][O:41][C:18]1[C:19]2[C:20](=[O:40])[N:21]([CH2:31][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28]=2[N:29]([CH3:30])[C:17]=1[C:15]([NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH3:43])=[O:16]
Reactant: COc1c(C(=O)NC2CCN(Cc3ccccc3)CC2C)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c(C(=O)NC2CCNCC2C)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
To a solution of the compound of Example 677 (373 mg, 0.65 mmol) in THF (40 mL) was added 1-chloroethyl chloroformate (0.67 mL, 6.5 mol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. 1-Chloroethyl chloroformate (0.67 mL, 6.5 mol) and diisopropylethylamine (0.30 mL, 3.2 mmol) were added under ice-cooling, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with diethyl ether. The residue was dissolved in methanol (50 mL), and the mixture was stirred at room temperature for 7 hr and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; methanol/ethyl acetate=0/100-10/90) and recrystallized from ethyl acetate-hexane to give the title compound (90 mg, 29%) as a pale-brown solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cn1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(N(C)c2ccc(OC)nc2)c2ccccc2n1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(6-methoxy-pyridin-3-yl)-methyl-amine (69 mg, 0.23 mmol) and 2.0 M methylamine in THF (4 ml, 8 mmol) by a procedure similar to example 38 to give 20 mg (30%) of yellow solids. 1H NMR (CDCl3): 8.02-8.01 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.42-7.34 (m, 2H), 6.97-6.94 (m, 1H), 6.76-6.70 (m, 2H), 5.01 (brs, 1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.12 (d, J=5.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].ClC(OCC)=O.[NH3:21]>C1COCC1>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C@H:11]1[C:12](=[O:14])[NH2:21])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: N
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
TEA (10.4 mL, 74.5 mmol) was added to a 0° C. solution of Boc-L-azetidine-2-carboxylic acid (7.50 g, 37.3 mmol) in THF (85 mL) and the resulting mixture was stirred at 0° C. for 20 min, before ethyl chloroformate (3.82 mL, 39.1 mmol) was added (exotherm). The rxn mixture was stirred at 0° C. for 20 min, then 25% aq. NH3 (62.7 mL, 447 mmol) in THF (25 mL) was added and the resulting mixture was allowed to reach rt and stirring was continued at rt for 45 min. The mixture was concentrated in vacuo to remove the solvent, the residue was taken up in DCM and water, the org. layer was separated and the inorg. layer was extracted with DCM (2×). The combined org. layers were dried (MgSO4), filtered and concentrated in vacuo to yield the title compound C-1 as a white solid which was used further without purification. LC-MS A: tR=0.52 min; [M+H]+=201.27.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: ClCCCBr
Product: ClCCCSc1ccc(Cl)cc1

Procedure:
Prepared by Procedure R and Scheme Z using 4-chlorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([CH:19]=[CH2:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([CH:19]=[CH2:20])[C:11]=2[N:12]=[C:13]([NH:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: C=Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Product: C=Cc1csc2c(NCc3ccccc3)nc(NCCN3CCOCC3)nc12
Yield: 78.5 %

Procedure:
The target compound of Example 46 (36 mg, 78% yield) was prepared in the same manner as Step 3 of Example 44 using N-benzyl-2-chloro-7-vinylthieno[3,2-d]pyrimidin-4-amine (35 mg, 0.116 mmol) and 2-morpholinoethanamine (75 mg, 0.58 mmol).
Reaction SMILES: C([C@@:3]12[N:10]([C:11](=[O:37])[CH:12]([NH:25][C:26](=[O:36])[C:27]3[CH:32]=[CH:31][C:30]([CH:33]=[N:34][NH2:35])=[CH:29][CH:28]=3)[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20]C(C)(C)C)=[CH:16][CH:15]=3)[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)C>C(Cl)Cl>[NH2:35][N:34]=[CH:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[C:11]([N:10]2[CH:7]3[CH2:8][CH2:9][C@@H:3]2[CH2:4][CH2:5][CH2:6]3)=[O:37])=[O:36])=[CH:32][CH:31]=1
Reactant: CC[C@]12CCCC(CC1)N2C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)c1ccc(C=NN)cc1
Solvent: ClCCl
Product: NN=Cc1ccc(C(=O)NC(Cc2ccc(O)cc2)C(=O)N2C3CCC[C@H]2CC3)cc1
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of 150 mg of ethyl (S)-8-[2-(4-aminoiminomethyl-benzoylamino)-3-(4-t-butoxyphenyl)propionyl]-8-azabicyclo[3.2.1]octan-endo-3-yloxyacetate hydrochloride is stirred at room temperature in 5 ml of CH2Cl2 and 2.5 ml of trifluoroacetic acid and evaporated. With ether the residue gives crystals which are filtered off under suction and dissolved in 5 ml of EtOH. 40 mg of NaOH dissolved in 1 ml of water are added to the solution and the mixture is stirred at room temperature. The reaction solution is neutralized with 1N hydrochloric acid and evaporated. Chromatography of the residue on silica gel RP-18 with water/THF gives 75 mg of (S)-8-[2-(4-aminoiminomethyl-benzoylamino)-3-(4-hydroxyphenyl)propionyl]-8-azabicyclo [3.2.1]octan-endo-3-yloxyacetic acid, MS: 495 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[OH:21][C@H:22]([CH2:40][O:41][CH3:42])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=O)=[C:32]([O:38][CH3:39])[CH:31]=2)[CH2:26][CH2:25]1>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([CH:27]4[CH2:26][CH2:25][N:24]([CH2:23][C@H:22]([OH:21])[CH2:40][O:41][CH3:42])[CH2:29][CH2:28]4)=[CH:31][C:32]=3[O:38][CH3:39])[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COC[C@@H](O)CN1CCC(c2ccc(C=O)c(OC)c2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COC[C@@H](O)CN1CCC(c2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)c(OC)c2)CC1
Yield: 47.1 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (109 mg, 0.373 mmol) and 4-[1-((S)-2-Hydroxy-3-methoxy-propyl)-piperidin-4-yl]-2-methoxy-benzaldehyde (126 mg, 0.410 mmol) were reacted to produce 102 mg (47%) of the title compound. mp: 189-191° C., 1H NMR (300 MHz, CDCl3): 10.67 (s, 1H), 8.35 (d, J=8 Hz, 1H), 8.04 (s, 1H), 7.04 (d, J=8 Hz, 1H), 6.94 (s, 1H), 6.39-6.35 (m, 3H), 5.51 (d, J=8 Hz, 1H), 5.19 (t, J=8 Hz, 1H), 5.07 (s, 1H), 4.08 (s, 3H), 3.89 (m, 1H), 3.19 (s, 2H), 2.98 (d, 1H), 2.91 (s, 1H), 2.88 (d, J=8 Hz, 1H), 2.62 (m, 1H), 2.46-2.22 (m, 5H). MS: 581 (M+H), HPLC: 1.90 min (G method).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[NH:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].P(Cl)(Cl)(Cl)=O.CN(C)[CH:23]=[O:24]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([CH:23]=[O:24])[C:11]([CH3:15])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CN(C)C=O
Reactant: Cc1cc(=O)n(-c2ccc(C)c(C)c2)[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-n2nc(C)c(C=O)c2O)cc1C
Temperature: 100 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
1.86 g (9.16 mmol) of 1-(3,4-dimethylphenyl)-3-methyl-3-pyrazolin-5-one was dissolved in 3.6 ml of dry dimethylformamide, and 1.02 ml (11.0 mmol) of phosphorus oxychloride was added gradually under cooling with ice at 20° C. or below. After the addition, the mixture was heated at 100° C. for 2 hours, then cooled to room temperature and poured into 30 ml of ice-cold water. Then, it was washed with 10 ml of water and 10 ml of dimethylformamide. The mixed solution was stirred for 18 hours, and the precipitated solid was collected by filtration, washed with 20 ml of water and dried to obtain 1.03 g of the above-identified desired product as a pale brown solid (yield 49%).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[OH:13]O>C(O)(=O)C>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[CH:12][C:2]([CH3:1])=[N+:3]([O-:13])[CH:4]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1ccc(C)nc1
Reactant: OO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(C)[n+]([O-])c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 14.9 g of ethyl 6-methylnicotinate, 60 ml of acetic acid and 21.5 ml of 30% hydrogen peroxide was stirred at 80° C. for 16 hours, the reaction liquid was concentrated under a reduced pressure, water was added to the concentrate, and the mixture was extracted with chloroform. The chloroform layer was washed with an aqueous solution of potassium carbonate and dried over anhydrous potassium carbonate, and the solvent was removed under a reduced pressure to obtain 14.0 g of 5-ethoxycarbonyl-2-methyl pyridine-1-oxide. ##STR6##
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](Cl)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].[Cl:17]CC(=O)CC1C=CC=CC=1Cl.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: O=C(CCl)Cc1ccccc1Cl
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)Cc1ccccc1Cl
Yield: 43 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(2-chlorophenyl)propan-2-one (0.556 g, 2.74 mmol) with acetic acid (0.31 mL, 0.33 g, 5.5 mmol) and triethylamine (0.76 mL, 0.56 g, 5.5 mmol). Flash chromatography over silica gel (5-40% ethyl acetate in hexanes) gave pure product (0.251 g, 43% yield): 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H) 3.88 (s, 2H) 4.75 (s, 2H) 7.24-7.27 (m, 3H) 7.38-7.42 (m, 1H).