Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=4)[N:17]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[N:16]=3)[N:13]=[CH:14][C:9]=2[NH:8][S:7]1(=[O:34])=[O:33].[C:41](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([C:15]3[C:23]4[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=4)[N:17]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])[N:16]=3)[N:13]=[CH:14][C:9]=2[N:8]([CH3:41])[S:7]1(=[O:34])=[O:33]
Reactant: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3NS2(=O)=O)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CN2c3nc(-c4nn(Cc5ccccc5F)c5ncc(F)cc45)ncc3N(C)S2(=O)=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg (approx. 0.115 mmol, 50% purity) of the compound from example 99A were initially charged in 5 ml of DMF, 44 mg (0.138 mmol) of cesium carbonate and 8.5 μl (0.138 mmol) of iodomethane were added and the mixture was stirred at RT overnight. Subsequently, another 14.3 μl (0.230 mmol) of iodomethane were added and the mixture was heated to 50° C. overnight. After cooling, the mixture was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). This gave 30.9 mg (46% of theory) of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[N:25][CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([N:27]([CH3:32])[S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=2)[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: CN(c1cncc(Br)c1)S(C)(=O)=O
Product: CN(c1cncc(C#Cc2cc(C#N)ccc2OCC(=O)O)c1)S(C)(=O)=O

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and N-(5-bromopyridin-3-yl)-N-methylmethanesulfonamide (Intermediate 33), the title compound was obtained as an off-white solid.
Reaction SMILES: [OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.[OH-].[K+:37]>C(#N)C.O>[OH:1][C@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O-:10])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1.[K+:37]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@@]3(O)CC[C@H](C(=O)[O-])C(C)(C)C3)s2)c1
Temperature: 35 °C

Procedure:
(1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (9.8 mg, 0.019 mmol) was dissolved in acetonitrile (20 μL) and water (20 μL). Potassium hydroxide (19 μL, 0.019 mmol) was added, and the mixture was heated to 35° C. for 10 min. The mixture was allowed to cool to room temperature, diluted with water, froze to a solid, and lyophilized to dryness to afford potassium (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate. MS ESI: [M+H]+ m/z 507.1. 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.83 (d, J=4.9, 1H), 7.91 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 7.27 (d, J=4.9, 1H), 7.12 (s, 1H), 5.97 (s, 2H), 2.31 (s, 3H), 1.92-1.82 (m, 2H), 1.81-1.65 (m, J=13.8, 5H), 1.54-1.48 (m, 1H), 1.47-1.39 (m, 1H), 1.05 (s, 3H), 0.95 (s, 3H). rhSYK activity=+++
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:21])[CH3:20])[CH:13]=2)[C:6](=[O:22])[N:5]([CH2:23][C:24]([OH:26])=O)[C:4]=1[CH3:27].[NH:28]1[C:36]2[C:31](=[CH:32][C:33]([CH2:37][NH2:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1>>[Cl:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([CH3:20])[CH3:21])[CH:13]=2)[C:6](=[O:22])[N:5]([CH2:23][C:24]([NH:38][CH2:37][C:33]2[CH:32]=[C:31]3[C:36](=[CH:35][CH:34]=2)[NH:28][CH:29]=[CH:30]3)=[O:26])[C:4]=1[CH3:27]
Reactant: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)O
Reactant: NCc1ccc2[nH]ccc2c1
Agent: Cl
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)NCc1ccc2[nH]ccc2c1
Yield: 95 %

Procedure:
The title compound was prepared by a similar method to preparation 9 from 2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetic acid hydrochloride (preparation 22) (85 mg, 0.20 mmol) and 1H-indol-5-ylmethylamine (preparation 8) (35 mg, 0.24 mmol) to give the title compound (100 mg, 0.19 mmol, 98%). 1H NMR (CD3OD) δ 2.20 (s, 3H), 2.70 (s, 6H), 3.00 (m, 2H), 3.60 (m, 2H), 4.20 (s, 2H), 4.50 (s, 2H), 4.80 (m, 2H), 7.05 (m, 1H), 7.10-7.55 (m, 9H), 7.75 (m, 1H), 7.85 (m, 1H). LRMS m/z=507.3, 509.3 (M+1)+.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ClCCl.C(C1C=C(CC[N:26]2[CH2:31][CH2:30][C:29]([CH2:33][N:34]([CH3:45])[C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=3)([OH:32])[CH2:28][CH2:27]2)C=CC=1)#N.[CH3:46][S:47]([C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([OH:59])=O)=[CH:52][CH:51]=1)(=[O:49])=[O:48]>O>[OH:32][C:29]1([CH2:33][N:34]([CH3:45])[C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[CH2:30][CH2:31][N:26]([C:57](=[O:59])[CH2:56][C:53]2[CH:52]=[CH:51][C:50]([S:47]([CH3:46])(=[O:48])=[O:49])=[CH:55][CH:54]=2)[CH2:27][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: COC(=O)c1ccc(N(C)CC2(O)CCN(CCc3cccc(C#N)c3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(N(C)CC2(O)CCN(C(=O)Cc3ccc(S(C)(=O)=O)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.8 %

Procedure:
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.68 g) was added to a dichloromethane solution (15 mL) of the compound (0.90 g) obtained in Step 3 of Example 25 and 4-methylsulfonylphenylacetic acid (0.76 g) and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into cold water (80 mL) and then separated, and the aqueous layer was extracted with dichloromethane. The organic layer was combined and washed with water and brine successively, and then dried over anhydrous sodium sulfate. After the solvent was removed under reduce pressure, the residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=8:1) to obtain the titled compound (1.36 g) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27]1)=[O:25].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:29]3[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]4[CH:22]=[C:21]([O:20][CH3:19])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=4)[CH2:27][CH:28]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: CCOC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (0.53 g) in dichloromethane (8 ml) is added dropwise, while stirring at 0° C. for 3 minutes, to a mixture of ethyl 4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (0.7 g), triethylamine (0.5 g) and dichloromethane (15 ml). The reaction mixture is stirred for 2 hours at room temperature, and then poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and water, successively, and dried, then the solvent is distilled off under reduced pressure. Crystals obtained from the residue are recrystallized from ethyl acetate and hexane to give ethyl 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate as colorless crystals (0.9 g), m.p. 108-110° C.
Reaction SMILES: C1(S[CH:8]=[CH:9][C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:11])C=CC=CC=1.C([O:29][C:30]1[CH:35]=[CH:34][C:33](C2C=CC=CC=2)=[CH:32][CH:31]=1)(=O)C#C.C1(O)C=CC=CC=1>>[O:29]([CH:8]=[CH:9][C:10]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:11])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(C=CSc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Reactant: C#CC(=O)Oc1ccc(-c2ccccc2)cc1
Solvent: Oc1ccccc1
Product: O=C(C=COc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Yield: 80 %

Procedure:
The compound 6 was prepared according to the method described for compound 4 employing compound 1 (435 mg, 2.15 mmol) and phenol (223 mg, 2.36 mmol) to give white solid compound 6 (510 mg, 80%). 1H NMR (300 MHz, CDCl3) δ 5.67 (d, J=12.2 Hz, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 7.33 (q, J=7.9 Hz, 5H), 7.49 (t, J=7.0 Hz, 5H), 7.92 (d, J=12.2 Hz, 1H). HRMS ESI (m/z): Calculated for C21H16O3 ([M+H]+): 317.1099. found: 317.1175.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:7][C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:3]=[N:2]1.[CH2:13]([Mg]Br)[CH3:14].C(OCC)C>C1COCC1>[NH:2]1[CH:3]=[C:4]([C:6]2[S:7][C:8]([CH:11]([OH:12])[CH2:13][CH3:14])=[CH:9][N:10]=2)[CH:5]=[N:1]1
Reactant: O=Cc1cnc(-c2cn[nH]c2)s1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1cnc(-c2cn[nH]c2)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
A solution of 2-(1H-pyrazol-4-yl)thiazole-5-carbaldehyde (245 mg, 1.3 mmol) in THF (15 mL) was cooled to 0° C., a 3M solution of ethyl magnesium bromide in diethyl ether (0.9 mL, 2.7 mmol) slowly added at 0° C., and the reaction mixture stirred for 2 hours at 0° C. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), dried over Na2SO4, filtered and the organic solvent was concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 3% methanol in dichloromethane) to afford 1-(2-(1H-pyrazol-4-yl)thiazol-5-yl)propan-1-ol as pale yellow liquid (180 mg, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.19 (br s, 1H), 8.25 (s, 1H), 7.88 (s, 1H), 7.51 (s, 1H), 5.59 (d, 1H), 4.71 (q, 1H), 1.97-1.64 (m, 2H), 0.86 (t, 3H); LC-MS m/z calculated for [M+H]+ 210.06, found 210.1.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[N:4]=1.[C-:27]#[N:28].[K+].O>CS(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)[N:4]=[C:3]2[CH2:2][C:27]#[N:28]
Reactant: [C-]#N
Reactant: COc1ccc(Cn2nc(CCl)c3cc(OC)c(OC)cc32)cc1OC
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(Cn2nc(CC#N)c3cc(OC)c(OC)cc32)cc1OC
Temperature: 25 °C
Yield: 60.9 %

Procedure:
In 1000 ml of dimethyl sulfoxide was dissolved 187.0 g of 3-chloromethyl-5,6-dimethoxy-1-(3,4-dimethoxybenzyl)-1H-indazole, followed by stirring at room temperature. To the solution was added 134.0 g of potassium cyanide, having been ground to powder in a mortar, followed by stirring at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into 15000 ml of water, and stirred for 1 hour. A precipitated solid was collected, washed with three 1000 ml portions of water, dissolved in 5000 ml of chloroform, dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography using 2 kg of silica gel and chloroform:ethanol=50:1 and then 2 kg of silica gel and ethyl acetate:hexane=3:1, to yield 111.0 g of a pale brown solid. This solid was used in the subsequent reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4][N:3]1[OH:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1C=CC=CC=1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4][N:3]1[O:12][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: O=c1c2ccccc2nnn1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CS(=O)(=O)On1nnc2ccccc2c1=O
Yield: 73.3 %

Procedure:
In benzene (30 ml) are dissolved 4-oxo-3,4-dihydro-3-hydroxy-1,2,3-benzotriazine (2.4 g) and triethylamine (2.1 ml) and thereto is added dropwise methanesulfonyl chloride (1.7 g), whereby faint exotherm occurs and crystals are precipitated. The reaction mixture is extracted with ethyl acetate (80 ml). The extract is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and then distilled to remove the solvent. The resulting residue is washed with ether-petroleum ether and dried to give 4-oxo-3,4-dihydro-3-methanesulfonyloxy-1,2,3-benzotriazine (2.6 g), melting point: 132°-134° C. Infrared spectrum: 1720, 1380, 1175 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:28])[C:9]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:19][C:18]=2[CH:27]=1)=[CH:10][N:11]([CH3:13])C.Cl.[CH2:31](N)C>O1CCCC1.O>[Cl:1][C:2]1[C:3]([CH3:29])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:28])[C:9]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[N:19][C:18]=2[CH:27]=1)=[CH:10][NH:11][CH2:13][CH3:31]
Reactant: CCN
Reactant: Cc1nsc(NC(=O)C(=CN(C)C)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNC=C(C(=O)Nc1snc(C)c1Cl)c1ccc2oc(CC(C)(C)C)nc2c1
Temperature: 60 °C
Yield: 85.4 %

Procedure:
A mixture of N-(4-chloro-3-methylisothiazol-5-yl)-α-[(dimethylamino)methylene]-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (0.20 g, 0.00046 mole) [from Example 5] and ethylamine hydrochloride (0.0225 g, 0.0028 mole) in tetrahydrofuran (4 ml) and water (1 ml) was heated for 24 hours at 60° C. The mixture was cooled to room temperature, the solvent was evaporated in vacuo and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. Further purification by flash column chromatography, eluting with ethyl acetate:hexane at 2:3 by volume, gave N-(4-chloro-3-methylisothiazol-5-yl)-α-[(ethylamino)methylene]-[2-(2,2-dimeth-ylpropyl)benzoxazol-5-yl]acetamide as a colourless solid (0.17 g). Analysis by 1H NMR showed the product comprised a mixture of E- and Z-isomers.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=2)[N:9]=1.[CH2:19]([S:25][CH2:26][C:27](O)=[O:28])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[NH2:17][C:16](=[N:15][C:12]1[S:13][CH:14]=[C:10]([C:8]2[N:9]=[C:5]([CH2:4][NH:3][C:27](=[O:28])[CH2:26][S:25][CH2:19][C:20]3[O:24][CH:23]=[CH:22][CH:21]=3)[S:6][CH:7]=2)[N:11]=1)[NH2:18]
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Reactant: O=C(O)CSCc1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(N)=Nc1nc(-c2csc(CNC(=O)CSCc3ccco3)n2)cs1
Yield: 11 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (1.6 g), (furfurylthio)acetic acid (0.98 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g) and triethylamine (1.0 g) in N,N-dimethylformamide (20 ml) was stirred with cooling on an ice-water bath for 2.5 hours. The solvent was removed under the reduced pressure. The residue was washed with water and then chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). The appropriate fractions was collected and the solvent was removed under the reduced pressure. The residue was suspended in water (20 ml) and the mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 2-(diaminomethyleneamino)-4-[2-(furfurylthio)acetylaminomethylthiazol-4-yl]thiazole (0.22 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:6]2[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][CH2:30][OH:31]>>[CH:16]1([N:13]2[C:6]3[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=3[CH:4]=[C:3]([CH2:2][O:31][CH2:30][CH2:29][O:28][CH3:27])[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CSc1ncc2cc(CBr)c(=O)n(C3CCCC3)c2n1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Bromomethyl-8-cyclopentyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.33 g, 3.75 mmol) was dissolved in 2-methoxyethanol (10 mL) to which potassium carbonate (0.778 g, 5.63 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the salts washed with ethyl acetate. The combined organics were evaporated to give 8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a waxy solid (1.00 g, 76.3%). 1H NMR δ (400 MHz, CDCl3) 8.60 (s, 1H), 7.71 (t, J=1.6 Hz, 1H), 5.95 (m, 1H), 4.52 (d, J=1.6 Hz, 1H), 3.76 (m, 2H), 3.63 (m, 2H), 3.41 (s, 3H), 2.60 (s, 3H), 2.32 (m, 2H), 2.06 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([CH3:8])([CH3:7])[C:4](O)=O.[NH2:11][NH:12][C:13]([NH2:15])=[S:14].P(Cl)(Cl)(Cl)=O>>[F:1][C:2]([F:10])([F:9])[C:3]([C:4]1[S:14][C:13]([NH2:15])=[N:12][N:11]=1)([CH3:8])[CH3:7]
Reactant: CC(C)(C(=O)O)C(F)(F)F
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(c1nnc(N)s1)C(F)(F)F

Procedure:
Commercially available, 3,3,3-trifluoro-2,2-dimethylpropanoic acid (Matrix), thiosemicarbazide (Aldrich) and phosphorus oxychloride (Aldrich) were processed as described for Example 1A to obtain the title compound. MS (ESI+) m/z 212 (M+H)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.[C:9]1([NH2:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[OH:5][C:4]1[CH:3]=[C:1]([CH:8]=[CH:7][CH:6]=1)[NH:19][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(O)c1
Reactant: Nc1cccc2ccccc12
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Product: Oc1cccc(Nc2cccc3ccccc23)c1
Yield: 86 %

Procedure:
Using the method described in Example 1, 220 parts of resorcinol, 286 parts of α-naphthylamine and 8 parts of triphenyl phosphite give 411 parts (86% of theory) of 3-hydroxy-N-naphthyl-aniline, of boiling point 225° - 227° C/2 mm Hg.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:23][CH2:22][N:21]3[C:14](=[CH:15][C:16]4[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=43)[C:13]2=[O:26])=[CH:10][C:9]([F:27])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]3[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48](B4OC(C)(C)C(C)(C)O4)[CH:49]=3)=[N:41][CH:42]=2)[CH2:33][CH2:32]1)[CH3:30].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[CH2:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]3[C:45](=[O:60])[N:46]([CH3:59])[CH:47]=[C:48]([C:7]4[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:11]([N:12]5[CH2:23][CH2:22][N:21]6[C:14](=[CH:15][C:16]7[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]=76)[C:13]5=[O:26])[CH:10]=[C:9]([F:27])[CH:8]=4)[CH:49]=3)=[N:41][CH:42]=2)[CH2:33][CH2:32]1)[CH3:30]
Reactant: CCN1CCN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, 189a (381.9 mg, 0.850 mmol), 3-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (201a) (560 mg, 1.275 mmol), Pd(PPh3)4 (49.1 mg, 0.043 mmol), Na2CO3 aqueous solution (1.0 N, 2.81 mL, 2.81 mmol), 1,2-dimethoxy-ethane (4 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 238a.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O.O.NN>C(O)C.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a mixture of 4.6 g of 2-(4-chloro-3-nitrophenyl) propionic acid and 250 mg of 10% palladium-on-charcoal in 50 ml of ethanol, was added dropwise 2.5 g of hydrazine hydrate under a stream of nitrogen. After the completion of the addition, the mixture was stirred at room temperature for one hour and then refluxed for 6 hours. The resulting mixture was cooled to room temperature, mixed with 250 mg of 10% palladium-on-charcoal and 2.5 g of hydrazine hydrate, and refluxed for 6 hours. After filtration, the filtrate was evaporated and dissolved in 20 ml of water. The aqueous solution was adjusted to pH 5-6 with 6 N hydrochloric acid and then concentrated to a volume of 20 ml. On standing overnight at room temperature, 3.0 g of 2-(m-aminophenyl)propionic acid was obtained; m.p. 98°-100° C.; Analysis--Calculated for C9H11NO2 : C 65.43%, H 6.71%, N 8.48%, Found C 65.41%, H 6.72%, N 8.48%.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH3:32])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[N:3]1[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=1
Reactant: C=CCOCC1(c2cccc(C)c2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOCC1(c2cccc(C)c2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[2,5-dioxo-4-(3-methylphenyl)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethylbenzonitrile (829 mg) in DMF (1.5 mL) is added potassium carbonate (320 mg) and methyliodide (480 μL). The mixture is stirred 3 hours at rt, evaporated, washed with brine, extracted with ethyl acetate, dried over MgSO4 and concentrated to give the desired compound.