Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][C:19]1[C:20]([CH2:25][OH:26])=[N:21][CH:22]=[CH:23][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:26][CH2:25][C:20]2[C:19]([CH3:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: Cc1cccnc1CO
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cccnc1COc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (3-methyl-pyridin-2-yl)methanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:9][NH:10][CH3:11]>CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([N:10]([CH3:11])[CH3:9])=[CH:4][CH2:3]1
Reactant: CNC
Reactant: CN1CCC(=O)CC1
Solvent: CCOCC
Product: CN1CC=C(N(C)C)CC1
Yield: 70 %

Procedure:
To 1000 g of Klinosorb-4 molecular sieve 500 ml of dry ether and 226 g of 1-methyl-4-piperidone are added and thereafter dimethylamine gas is bubbled into the reaction mixture with a rate allowing only slow reflux of the mixture in the initial period of the reaction. The dimethylamine gas is introduced into the reaction medium for 8 hours on three subsequent days, thereafter the mixture is filtered, the Klinosorb is washed with ether and the combined etheral solution is evaporated to dryness under reduced pressure. The oily residue is purified by distillation in vacum to yield 70% of 1-methyl-4-dimethylamino-1,2,5,6-tetrahydropyridine; bp.: 78°-82° C./2.66 kPa.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14].II.[NH3:17]>O1CCCC1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:17])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[O:13][CH3:14]
Reactant: N
Reactant: COc1c(O)ccc(C=O)c1[N+](=O)[O-]
Agent: II
Solvent: C1CCOC1
Product: COc1c(O)ccc(C#N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a mixture of 4-hydroxy-3-methoxy-2-nitrobenzaldehyde 14.5 g (73.5 mmol) in 28% ammonia solution 150 mL and tetrahydrofuran 15 mL was added iodine 22.4 g (88.2 mmol) and stirred at room temperature for overnight. The reaction mixture was concentrated in vacuo. The residue was acidified with 2H HCl solution and extracted into diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtrated and the solvent was evaporated. The residue was washed with diisopropyl ether to give the title compound 12.1 g as brown solid. Yield 84.5%
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23].CN(C)[CH:35]=[O:36]>O1CCCC1>[F:13][C:14]1[C:19]([CH:35]=[O:36])=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]
Reactant: CN(C)C=O
Reactant: CCc1ccc(S(=O)(=O)Nc2ccc(F)cc2F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(F)c(C=O)c2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
To N,N-diisopropylamine (4.50 mL, 32.1 mmol) in 130 mL of tetrahydrofuran, n-butyllithium (12.8 mL, 2.50 M in hexane, 32.1 mmol) is added at −78° C. under nitrogen. After 15 minutes, N-(2,4-difluoro-phenyl)-4-ethyl-benzenesulfonamide (60, 4.344 g, 14.61 mmol) in 20 mL of tetrahydrofuran is added at −78° C. under nitrogen. After 30 minutes, N,N-dimethylformamide (2.83 mL, 36.5 mmol) is added and the reaction continued at −78° C. under nitrogen for 1 hour, then warmed to room temperature over 60 minutes. The reaction is quenched with 6 mL of 6 N aqueous hydrochloric acid. The aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with a gradient of 5-35% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (61, 2.634 g). MS (ESI) [M−H+]−=324.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][C:15]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:16]=2[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[S:14][C:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[S:10])[CH:7]=1
Reactant: Nc1nc2ccc3ccccc3c2s1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1ccc(Cl)cc1NC(=S)Nc1nc2ccc3ccccc3c2s1
Yield: 21.9 %

Procedure:
Prepared using Method A from 5.0 g (27.2 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 5.0 g (25 mmol) of 2-amino-naptho[2,1-d]thiazole to give 2.1 g of title compound as an off-white solid, (21% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:11].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Cc1c(O)ccc2occc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(O)ccc2c1CCO2

Procedure:
A solution of 35 (1.86 g, 12.6 mmol) in absolute ethanol (50 mL) was hydrogenated over 10% palladium on carbon catalyst (0.10 g) at 3 atmospheres pressure. After the required amount of hydrogen had been taken up (overnight) the catalyst was removed by filtration and washed with an additional portion of absolute ethanol (20 mL). The combined filtrate and washings were concentrated to a white crystalline solid (1.88 g). Recrystallization from toluene gave 36.
Reaction SMILES: [N:1]1([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl[C:10]1[CH:15]=[C:14]([S:16][CH:17]2[CH2:22][O:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][CH2:18]2)[N:13]=[C:12]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])[N:11]=1>>[F:38][C:32]1[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][S:29][C:12]1[N:11]=[C:10]([NH:8][S:5]([N:1]2[CH2:4][CH2:3][CH2:2]2)(=[O:7])=[O:6])[CH:15]=[C:14]([S:16][CH:17]2[CH2:18][O:19][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:21][CH2:22]2)[N:13]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(SC3COC(c4ccccc4)OC3)n2)c1F
Reactant: NS(=O)(=O)N1CCC1
Product: O=S(=O)(Nc1cc(SC2COC(c3ccccc3)OC2)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
The subtitle compound was prepared from azetidine-1-sulfonamide (prepared according to patent WO 2004/011443, 0.11 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(2-phenyl-1,3-dioxan-5-yl)thio]pyrimidine (the product of step i) (0.17 g) according to the procedure outlined in Example 1, step iv). The residue was purified by flash chromatography on silica gel, eluting with EtOAc/iso-hexane (2:8) to give the subtitle compound as a colourless oil. Yield: 0.11 g
Reaction SMILES: [C:1]1([C:6](Cl)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1>C1C=CC=CC=1>[C:1]1([C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]([CH3:23])[CH2:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][CH:11]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Solvent: c1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)c2cccs2)cc1
Yield: 51.9 %

Procedure:
A mixture of 1.1 g of 2-thenoyl chloride, 1.0 g of 6-(p-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 10 ml of benzene was treated in the same manner as described in Example 1 to effect reaction whereby 800 mg of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]=[C:7]([NH:9][C@H:10]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][C:24]4[NH:25][CH2:26][CH2:27][CH2:28][N:29]=4)=[CH:14][CH:13]=3)[S:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:39]=[CH:38][C:5]2[N:6]=[C:7]([NH:9][C@H:10]([C:31]([OH:33])=[O:32])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:30])[NH:23][C:24]4[NH:25][CH2:26][CH2:27][CH2:28][N:29]=4)=[CH:14][CH:13]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccc(Br)cc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)O)cc1)NC1=NCCCN1
Yield: 136.4 %

Procedure:
Hydrolysis of the ester is carried out as in the previous examples, but starting from 50 mg of 8-3 and twice 0.5 ml of TFA in 1.5 ml dichloromethane. 62 mg of 8-4 is obtained (in the form of the trifluoroacetic acid salt).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH:24]1[C:28]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)=[N:27][N:26]=[N:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH:18]([CH3:19])[CH3:20])[C:15]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([C:28]4[NH:27][N:26]=[N:25][N:24]=4)=[CH:30][CH:31]=3)=[O:17])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Reactant: CC(C)C(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C)C(C(=O)Nc1ccc(-c2nnn[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
79 mg (purity 86%, 0.21 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-methylbutanoic acid (racemate) (Example 4.1C) and 40 mg (0.25 mmol) of 4-(1H-tetrazol-5-yl)aniline were reacted according to General Method 1. Yield: 45 mg (46% of theory)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:16]3[C@@H:17]4[C@@H:22]([C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[CH2:19][CH2:18]4)[CH2:13][CH2:14][CH2:15]3)=[O:12])=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]nnc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 58 %

Procedure:
The title compound is prepared from 1H-benzotriazole-5-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 58% of theory; LC (method 4): tR=1.90 min; Mass spectrum (ESI+): m/z=333 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:33]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])[CH3:34]>O1CCCC1>[CH2:33]([O:35][C:36]([N:38]1[CH2:39][CH2:40][N:41]([C:18](=[O:20])[CH2:17][N:16]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:42][CH2:43]1)=[O:37])[CH3:34]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'carbonyldiimidazole (2.82 g, 0.0174 mole), and dry tetryhydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of ethyl-1-piperazine carboxylate (6.9 g, 0.0435 mole) in tetrahydrofuran (6 ml) was added dropwise and the reaction mixture was stirred at 50° C. overnight under nitrogen. The solvents were removed under reduced pressure and the residual oil was triturated in water (100 ml) overnight. The resulting solid was collected by filtration, rinsed with water, dissolved in hot isopropyl alcohol, and filtered hot. Water was added to the cloud point and upon cooling to room temperature, a solid precipitated, which was collected by filtration, rinsed with water, and dried uner high vacuum to give 4.66 g (63%) of title compound, mp 184°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8]1)=[O:6].Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:5]([N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH2:14])[CH2:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 183.8 %

Procedure:
Intermediate 30 (0.770 g) was treated with 4.0M hydrogen chloride in dioxane (8 ml). The mixture was stirred at 20° C. for 30 min. The solvent was removed in vacuo to give the title compound as a white solid (0.592 g).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([N:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[C:25]1([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:34]5([C:32]([NH:31][C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)=[O:33])[CH2:36][CH2:35]5)=[O:38])=[CH:3][C:4]=4[F:24])=[CH:12][N:11]3[N:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nc2ccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccccc5)CC4)cc3F)cn2n1)C1CC1
Yield: 80 %

Procedure:
Using N-[6-(4-amino-2-fluorophenoxy) [1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (120 mg, 0.367 mmol), 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (90.4 mg, 0.440 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (126 μL, 0.733 mmol) and HATU (209 mg, 0.550 mmol) and in the same manner as in Example 24, the title compound (151 mg, 80%) was obtained as white crystals.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1>CO>[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([C:21]([NH:2][NH2:3])=[O:23])=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Reaction time: 95 h
Yield: 61 %

Procedure:
80% Hydrazine monohydrate (0.17 mL, 2.8 mmol) was added to methyl 5-[3-(pyridin-4-yl)propylcarbamoyl]thiophene-2-carboxylate (0.28 g, 0.92 mmol) in methanol (10 mL), and the reaction solution was left at 50° C. for 95 hours. After addition of 80% hydrazine monohydrate (0.17 mL, 2.8 mmol), it was left at 55° C. for another 14 hours and concentrated to dryness by evaporating the solvent under reduced pressure. Methanol (2 mL) was added to the residue, and the resulting solution was put on a sonicator. The precipitated solid was recovered by filtration and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (yield 61%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:35]([CH:32]4[CH2:34][CH2:33]4)(=[O:37])=[O:36])[CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CN2CCN(S(=O)(=O)C3CC3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To 2-chloro-7-methyl-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (100 mg) in anhydrous DCM (2 ml) and triethylamine (1.5 equiv., 60 μl) at 0° C. was added cyclopropanesulfonyl chloride (1.1 equiv., 31 μl) and the reaction mixture was allowed to warm up to room temperature overnight. DCM/brine extraction and purification on silica gave 2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (101 mg).
Reaction SMILES: [CH2:1]([C:3]([CH:12]([CH3:30])[C:13](=[O:29])[C:14]1[CH:28]=[CH:27][C:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:20][C:16]=2[CH:15]=1)([C:8]([O:10]C)=[O:9])[C:4]([O:6]C)=[O:5])[CH3:2].[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([C:3]([CH:12]([CH3:30])[C:13](=[O:29])[C:14]1[CH:28]=[CH:27][C:17]2[N:18]=[C:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:20][C:16]=2[CH:15]=1)([C:4]([OH:6])=[O:5])[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCC(C(=O)OC)(C(=O)OC)C(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(=O)O)(C(=O)O)C(C)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
660 mg (1.13 mmol) dimethyl 2-ethyl-2-[1-methyl-2-oxo-2-(2-phenyl-benzoxazol-6-yl)-ethyl]-malonate are dissolved in 20 ml dioxane. Then 170 mg (7.10 mmol) lithium hydroxide, dissolved in 5 ml of water, are added and the mixture is stirred overnight at RT. The reaction mixture is extracted with DCM, the aqueous phase is acidified and extracted again with DCM. Then the org. phase is dried and the solv. is completely eliminated by rotary evaporation i.V. The residue is separated by RP-HPLC (basic).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:7]([C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[C:10]([F:13])([F:12])[F:11])=[O:9]
Reactant: CNOC
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1nc(C)oc1C(F)(F)F
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid (500 mg, 2.56 mmole) in dichloromethane (5 ml) was subsequently treated at 22° C. with N,O-dimethylhydroxylamine hydrochloride (262 mg, 2.69 mmole), N-methylmorpholine (0.29 ml, 2.69 mmole) and EDCI.HCl (516 mg, 2.69 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried and evaporated to give the title compound (559 mg) as a colorless oil which was used without further purification. MS: m/z=239.0 [M]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C:6]1[N:7]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1.[CH:24]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH2:25].O>O1CCCC1>[CH3:3][O:4][CH2:5][C:6]1[N:7]([CH2:19][C:20]([CH3:23])([O:22][CH2:25][CH2:24][S:26]([CH3:29])(=[O:28])=[O:27])[CH3:21])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1
Reactant: COCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1nc2cnc3ccccc3c2n1CC(C)(C)OCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 59 mg, 1.47 mmol) was added to a stirred solution of 1-[2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (4.20 g, 14.7 mmol) in tetrahydrofuran (59 mL). After 5 minutes, methyl vinyl sulfone (3.10 g, 29.4 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 17 hours. Water (5 mL) was added and the mixture was concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 3.7 g of 2-(methoxymethyl)-1-{2-methyl-2-[2-(methylsulfonyl)ethoxy]propyl}-1H-imidazo[4,5-c]quinoline as a white solid.
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:15]=1[NH2:16].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:11][C:10]1[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[F:13])=[C:3]([CH:7]=[CH:8][C:9]=1[F:12])[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: Cc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(Nc2c(C(=O)O)ccc(F)c2F)c(F)c1

Procedure:
2,3,4-Trifluorobenzoic acid and 2-fluoro-4-methylaniline were reacted in the presence of LiHMDS solution in THF by the general procedure of Example 1, Step B. After workup, 3,4-difluoro-2-[2-fluoro-4-methylanilino]benzoic acid was isolated as a crude pale brown solid which was reacted directly with 2-(aminooxy)ethanol and DMT-MM by the general procedure of Example 6, Step B below, then purified by column chromatography on silica gel (100% EtOAc as eluant) to give 3,4-difluoro-2-(2-fluoro-4-methylanilino)-N-(2-hydroxyethoxy)benzamide as a white solid (44%); m.p. (EtOAc/hexane) 134–139° C. 1H NMR [400 MHz, (CD3)2SO] [ ] 11.82 (v br s, 1H), 8.77 (br s, 1 H), 7.41 (ddd, J=8.1, 5.7, 1.6 Hz, 1 H), 7.13–7.00 (m, 2 H), 6.88 (dd, J=8.3, 1.1 Hz, 1 H), 6.82 (ddd, J=8.5, 8.5, 4.2 Hz, 1 H), 4.76 (v br s, 1 H), 3.86 (t, J=5.0 Hz, 2 H), 3.58 (J=5.0 Hz, 2 H), 2.25 (s, 3 H). Anal. calcd. for C16H15F3N2O3: C, 56.5; H, 4.4; N, 8.2. Found C, 56.3; H, 4.5; N, 8.2.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.C(O)CO.[OH-].[K+]>O>[Cl:22][C:17]1[CH:16]=[C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21

Procedure:
A mixture of N-[3-[(3,4-dichlorobenzoyl)amino]-2-pyridinyl] glycine ethyl ester (33 g, 0.09 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40 ml of water was added and the reaction mixture was heated at reflux for 1 hr. The solution was filtered to remove yellow insoluble precipitate, the filtrate was diluted with 650 ml of water, and acidified with ethanolic hydrogen chloride. The solid, which formed, was collected by filtration, washed with water, and dried under high vacuum first at 50° C. overnight, then at 70° C. for 21/2 days to give 25.3 g (98%), mp 248°-49° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C(Cl)Cl>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][N:38]([S:17]([C:13]2[S:14][C:15]([Br:16])=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[CH:12]=2)(=[O:19])=[O:18])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)sc2Br)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (400 mg; 0.96 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The solution is cooled down to 0° C. and put under nitrogen. Triethylamine (0.54 ml; 1.92 mmol; 4 eq) and 1-Boc-piperazine (358.4 mg; 1.92 mmol; 2 eq) are added successively and the reaction mixture is stirred at 0° C. for 1 hour. The reaction mixture is washed with water, NaHCO3 and dried over MgSO4, affording the title compound (440 mg; 76%).