Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.[C:16](=[S:18])=[S:17].[OH-].[Na+:20]>C(O)C>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:16]([S-:18])=[S:17].[Na+:20]
Reactant: S=C=S
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC[C@@H]1Cc2c([nH]c3ccccc23)CN1C(=S)[S-]
Reaction time: 2 h
Yield: 71 %

Procedure:
To a mixture of (3S)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (5.06 g), CS2 (2.0 g) and ethanol (230 ml) is added dropwise a 1N NaOH solution (25 ml) at room temperature. The mixture is stirred for 2 hours, and thereto is added ethanol. The precipitated crystals are collected by filtration and recrystallized from water-ethanol to give the title compound (5.3 g, 71%) as colorless needles, m.p. 209°-210° C. (decomp.), [α]D20 +151.8° (c=1, methanol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][N:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)[N:3]=1.Cl.[CH:30]([NH2:32])=[NH:31].C(N(CC)CC)C>CN(C=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][N:14]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[C:12]([C:4]2[N:3]=[C:2]3[NH:32][CH:30]=[N:31][C:8](=[O:10])[C:7]3=[CH:6][N:5]=2)=[N:13]1
Reactant: N=CN
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1nc[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc12
Reaction time: 8 h

Procedure:
150 mg (0.38 mmol) of methyl 4-chloro-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carboxylate (example 106A) and 78.5 mg (0.75 mmol) of formamidine hydrochloride were initially charged in 1.5 ml of DMF. Subsequently, 260 μl (1.89 mmol) of triethylamine were added and conversion was effected at 80° C. overnight. After cooling, the precipitated solid was filtered off and the mother liquor was then purified by means of preparative HPLC [column: Reprosil C18, 10 μm, 250*40 mm; eluent: acetonitrile/0.05% formic acid; gradient: 10% acetonitrile→>90% acetonitrile]. Thus, 65 mg (46% of theory) of the target compound were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][OH:20])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][O:20][C:22]3[CH:54]=[CH:53][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:52])=[CH:24][CH:23]=3)[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccc(F)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccc(F)cc2)cc1
Yield: 89.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 547 mg of 2-[1-(4'-fluorobiphenyl-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 27), 931 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 366 mg of diethyl azodicarboxylate, 1.29 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=2[N:6]=[C:5]1Cl)[CH:2]=[CH2:3].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:5]2[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]3[C:11](=[O:13])[NH:10][C:9](=[O:14])[N:8]([CH3:15])[C:7]=3[N:6]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: C=CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Yield: 85.7 %

Procedure:
7-Allyl-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (420 mg) and 1-piperazine carboxylic acid tert-butyl ester (975 mg) were stirred at 150° C. for 50 minutes. After cooling to room temperature, the resulting reaction mixture was purified by silica gel column chromatography to obtain 584 mg of the title compound from a fraction eluted with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.CS[C:20]1[NH:26][C:24](=[O:25])[CH:23]=[CH:22][N:21]=1>N1C=CC=CC=1>[O:25]=[C:24]1[CH:23]=[CH:22][NH:21][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[CH:16][CH:17]=2)=[N:26]1
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(N)cc1
Reactant: CSc1nccc(=O)[nH]1
Solvent: c1ccncc1
Product: CCOC(=O)CC(C)C(=O)c1ccc(Nc2nc(=O)cc[nH]2)cc1

Procedure:
A stirred mixture of ethyl 3-(4-aminobenzoyl)butyrate and 2-methylthiouracil in dry pyridine are heated together to afford the title compound.
Reaction SMILES: C=O.O.[C:4]([NH:8][CH:9]=[N:10][C:11]([NH2:13])=[O:12])(=[O:7])[CH:5]=[CH2:6].[CH3:14][O:15]C1C=CC(O)=CC=1>C(N(CC)CC)C>[CH2:14]([CH:6]=[CH:5][C:4]([NH:8][CH:9]=[N:10][C:11]([NH2:13])=[O:12])=[O:7])[OH:15]
Reactant: C=CC(=O)NC=NC(N)=O
Reactant: COc1ccc(O)cc1
Agent: C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)N=CNC(=O)C=CCO

Procedure:
11.34 g of a 37% strength aqueous solution of formaldehyde, 40 g of water, 20 g of acrylamidomethyleneurea, 50 mg of hydroquinone methyl ether and 0.2 g of triethylamine are introduced into a 250-ml reactor. The reaction mixture is heated for 1 hour to 60° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH2:15][S:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:33]=2)[CH2:26][CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=[CH:19][C:18]1=2>ClCCl>[CH3:8][S:9]([O:13][CH2:14][CH2:15][S:16][C:17]1([C:29]2[N:30]=[CH:31][N:32]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:33]=2)[C:18]2[C:23](=[CH:22][C:21]([C:27]#[N:28])=[CH:20][CH:19]=2)[CH2:24][CH2:25][CH2:26]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc2c(c1)CCCC2(SCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCSC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CCCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5 mmol of triethylamine and 2 mmol of methanesulphonyl chloride are added to a solution of 1 mmol of 5-(2-hydroxyethylsulphanyl)-5-(1-trityl-1H-imidazol-4-yl)-5,6,7,8-tetrahydro-naphthalene-2-carbonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloromethane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is identified on the basis of the Rf and used without further purification in the next stage.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[N:22]1[CH:23]=[CH:24][C:19]([C:18]([N:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:16])=[O:25])=[CH:20][CH:21]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)C1CCCN1C(=O)c1ccncc1
Temperature: 10 °C
Reaction time: 5 h

Procedure:
L-Proline benzyl ester hydrochloride (2.42 g, 0.01 mol) dissolved in pyridine (80 ml) is treated in portions at 3° C. (ice-bath cooling) with isonicotinoyl chloride hydrochloride (1.78 g, 0.01 mol), the IT increasing to 10° C. After removing the ice bath, the mixture is stirred for 5 h, the batch turning greenish.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[C:14]([Cl:15])=[N:13][S:12][N:11]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH2:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[C:14]([Cl:15])=[N:13][S:12][N:11]=1)=[N+:17]=[N-:18]
Reactant: Clc1ccc(-c2nsnc2Cl)c(CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(Cl)ccc1-c1nsnc1Cl

Procedure:
A solution of 3-[2-(bromomethyl)-4-chlorophenyl]-4-chloro-1,2,5-thiadiazole (0.193 g, 0.60 mmol) and sodium azide (38.7 mg, 0.60 mmol) in DMF (0.6 mL) was stirred at 60° C. for 16 h. The solution was partitioned between water and ether. The organic phase was separated, washed with brine, dried (Na2SO4) and reduced in vacuo. 3-[2-(Azidomethyl)-4-chlorophenyl]-4-chloro-1,2,5-thiadiazole was isolated as an oil. MS m/z=258.5.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5]([Cl:10])[N:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[NH2:16].C(Cl)Cl.[K+].[Br-]>>[CH3:21][O:20][C:18]1[CH:17]=[C:15]([NH:16][C:7]2[N:8]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([Cl:10])[N:6]=2)[CH:14]=[C:13]([O:12][CH3:11])[CH:19]=1
Reactant: CNc1nc(Cl)nc(Cl)n1
Reactant: COc1cc(N)cc(OC)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Cl)nc(Nc2cc(OC)cc(OC)c2)n1
Yield: 73 %

Procedure:
The title compound was synthesized from 2-methylamino-4,6-dichloro-1,3,5-triazine and 3,5-dimethoxyaniline using a similar procedure to the one used in 2. Yield: 73%; Tm 240° C.; FTIR (CH2Cl2/KBr) 3338, 3254, 3136, 3118, 3001, 2955, 2939, 2907, 2838, 1638, 1614, 1583, 1560, 1536, 1484, 1468, 1455, 1431, 1422, 1397, 1384, 1273, 1251, 1228, 1206, 1191, 1176, 1151, 1127, 1072, 1064, 986, 923, 874, 846, 836, 805, 795, 739, 717, 683 cm1; 1H NMR (300 MHz, DMSO-d6, 298K) δ 10.02, 9.84 (s, s, 1H), 8.12, 8.00 (s, s, 1H), 7.08, 7.00 (s, s, 2H), 6.19 (s, 1H), 3.71 (s, 6H), 2.85, 2.80 (s, d, 3J=4.7 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 168.3, 167.5, 165.8, 165.7, 163.6, 163.0, 160.2, 140.6, 140.5, 98.5, 98.1, 94.9, 94.5, 54.9, 27.4, 27.2 ppm; HRMS (EI) calcd. for C12H14ClN5O2 (m/e): 295.0836. found: 295.0843.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Br:10]Br>CCOCC>[Br:10][CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: BrBr
Reactant: CCOC(=O)CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)CC(=O)CBr
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
To a mechanically-stirred solution of ethyl acetoacetate (59 mL, 463 mmol) in ether (75 mL) was added bromine (23.5 mL, 912 mmol) while the reaction temperature was maintained below 23° C. using an ice-water bath. The yellow-orange solution was stirred for 5 hours with cooling and then was stirred overnight at ambient temperature. Ice (60 g) was added and the reaction mixture was extracted with ether. The organic phase was washed twice with aqueous NaHCO3 saturated with NaCl and once with brine. The ether solution was stirred for 1 day over CaCl2 and then was filtered through celite. The filter cake was rinsed with dichloromethane. The filtrate was concentrated in vacuo to give ethyl 4-bromoacetoacetate (71.5 g) which was stored in the dark and stabilized with BaCO3 (300 mg).
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][Cl:29].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCBr
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCCl)c1=O
Yield: 95 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep128, 2.5 g, 7.3 mmol), K2CO3 (1 g, 7.3 mmol) and 1-bromo-4-chloro-butane (1.26 ml, 10.95 mmol) were suspended in dry DMF (10 ml). After stirring the reaction at room temperature overnight, further 1-bromo-4-chloro-butane (840 μl, 7.3 mmol) was added. Water was added and the mixture was extracted with ethyl ether. The organic phase was dried (Na2SO4), filtered and evaporated; the crude was purified by flash chromatography with petroleum ether-ethyl acetate (7-3) to give the title compound as a white solid (3 g, 98% yield).
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=O)[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].O.NN>C(O)C>[C:1]([C:4]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[S:14][C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C1Cc2c(cccc2C(=O)O)Sc2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1CCc1ccccc1S2
Reaction time: 2 h
Yield: 42.2 %

Procedure:
The mixture of 1.0 g of 9-carboxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin, 1.0 g of hydrazine hydrate and 30 ml of ethanol was heated under reflux on water bath for 4 hours. The reaction mixture was concentrated to about 15 ml to separate crystals on cooling, which were collected by filtration. They were added to the mixture of 1.0 g of sodium hydroxide and 20 ml of diethylene glycal and the resulting mixture was heated with stirring at 190°-200° C. for 2 hours. After cooling, 300 ml of water was added to the mixture, which was extracted with diethyl ether. The aqueous layer was acidified with conc. hydrochloric acid and extracted with chloroform, and the solvent was evaporated therefrom. The thus obtained residue was chromatographed over silica gel and eluted with benzene-ethyl acetate (1:1), and there was obtained 0.4 g of 9-carboxy-10,11-dihydrodibenzo[b,f]thiepin as yellow prismatic crystals having a melting point of 186°-187° C.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[N:14]=2)[CH2:7]1)(=O)=O.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:16])[N:14]=2)[CH2:9]1)(=[O:26])[CH3:24]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (346 mg, 1.00 mmol) (obtained as described in Reference Example 27(3)) in dimethylformamide (15 ml) was added potassium thioacetate (687 g, 6.01 mmol) at room temperature. The reaction mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-acetylthio-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (276 mg, yield 85%) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][CH:5]=[CH:6][C:7](=[O:9])[N:8]=1.C1C(=O)N([I:17])C(=O)C1>CN(C=O)C.O>[I:17][C:6]1[C:7](=[O:9])[N:8]=[C:3]([O:2][CH3:1])[NH:4][CH:5]=1
Reactant: COc1nc(=O)cc[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(=O)c(I)c[nH]1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
2-Methoxypyrimidin-4(1H)-one (1.00 g, 7.93 mmol) and n-iodosuccinimide (3.57 g, 15.86 mmol) were mixed in DMF (8 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 70° C. for 2.5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting solid was suspended in DCM, filtered, and washed with DCM to give 5-iodo-2-methoxypyrimidin-4(1H)-one. [M+1]=252.9.
Reaction SMILES: [CH3:1][C:2]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]>[Fe].C(O)(=O)C>[NH2:18][C:17]1[C:2]([CH3:1])=[C:3]([CH:14]=[CH:15][CH:16]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: Cc1c(C(=O)OCc2ccccc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1c(N)cccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Iron powder was added to an acetic acid solution of benzyl 2-methyl-3-nitrobenzoate, followed by stirring at room temperature for 1.5 hours. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. This was diluted with ethyl acetate, neutralized with an aqueous saturated sodium hydrogencarbonate solution, and the insoluble matter was separated by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate was added and a solution of 4 M hydrogen chloride/ethyl acetate was dropwise added thereto at 0° C. The precipitate was collected by filtration to obtain benzyl 3-amino-2-methylbenzoate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH:20][C:21](=[O:33])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]#[N:32])[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:33]=[C:21]1[CH2:22][C:23]([C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[C:31]#[N:32])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:10][C:9]=2[NH:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccccn4)cc3NC(=O)C2)c1

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-pyridin-2-yl-phenyl}-carbamic acid tert.-butyl ester (Example K13) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a brown powder (29 mg).
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[CH:37]([C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43])([CH3:39])[CH3:38]>CN(C=O)C>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:40]([CH:37]([CH3:39])[CH3:38])[CH:41]=2)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: CC(C)c1cccc(N)c1
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cnc5ccccc45)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.10 mmol, 30 mg) and triethylamine (0.20 mmol, 0.028 mL) in 1.0 mL DMF at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.12 mmol, 0.072 mL). After 15 min at rt, 3-isopropylaniline (0.15 mmol, 0.021 mL) was added and the reaction stirred at rt for 4 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with EtOAc/hexane to give the title compound as a light beige solid (22 mg, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][C:6]2([CH3:14])[CH3:13].[CH:15](O)=[O:16].Cl.CN(C)CCCN=C=NCC>ClCCl.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH:15]=[O:16])[CH2:7][C:6]2([CH3:14])[CH3:13]
Reactant: COc1ccc2c(c1)C(C)(C)CNC2
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)C(C)(C)CN(C=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of 6-methoxy-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline (Intermediate 18, 3.2 g, 16.7 mmol) in anhydrous dichloromethane (40 mL) was treated with formic acid (1 mL, 26.5 mmol) followed 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.9 g, 20.34 mmol) and the resulting solution was stirred at ambient temperature overnight. It was then diluted with chloroform and washed with water (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as pale brown viscous oil (3.26 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][C:16]([OH:18])=O)[N:14]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]2[CH2:31][CH2:30][N:29]([C:16](=[O:18])[CH2:15][C:13]3[N:14]=[C:10]([NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[S:11][CH:12]=3)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)s2)n1
Reactant: CN1CCN(C2CCNCC2)CC1
Product: CN1CCN(C2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)s4)n3)CC2)CC1

Procedure:
53.2 Using general method A, {2-[(5-chloro-thiophene-2-carbonyl)-amino]-thiazol-4-yl}-acetic acid was coupled with 1-methyl-4-(piperidin-4-yl)-piperazine to give 5-chloro-thiophene-2-carboxylic acid (4-{2-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide. Light yellow amorphous solid. MS 468.4 ([M+H]+)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH2:25])=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:10]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:22][C:21]=1[CH3:26])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Benzoyl chloride (0.04 mL, 0.36 mmol) was added to a mixture of 2-amino-4-methylthiazole-5-carboxylic acid benzylamide (0.083 g, 0.033 mmol), 4-dimethylamino-pyridine (10 mg) and triethylamine (0.06 mL, 0.43 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 8 h, then concentrated. The residue was purified by column chromatography to afford the title compound in 75% yield (87 mg); 1H NMR (CDCl3, 300 MHz) δ 7.90-7.24 (m, 11H), 5.97 (s, br, 1H), 4.59 (d, J=5.8 Hz, 2H), 2.45 (s, 3H); MS (ES+) m/z 352.0 (M+1).