Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:12]([CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](O)=[O:18])(=[O:14])=[O:13])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:3].C1([N:33]=C=NC2CCCCC2)CCCCC1.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.CN(C)C=O>[CH3:1][C:2]([S:12]([CH2:15][CH:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([NH2:33])=[O:18])(=[O:14])=[O:13])([C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5])[CH3:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)N1CCOCC1)S(=O)(=O)CC(Cc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Analogously to the procedure described by Wang et al. in Synthesis 1989, 37 a mixture of 15.34 g (40mmol) of (S)-α-[[[(1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamic acid, 9.29 g (40 mmol) of dicyclohexylcarbodiimide and 6.89 g (50 mmol) of HOBT in 160 ml of methylene chloride and 40 ml of dimethylformamide was stirred at room temperature for 4 hours. Thereafter, the reaction mixture was filtered, the yellowish solution obtained was diluted with 200 ml of methylene chloride and cooled to 0°. Ammonia was conducted into this solution until it was saturated. The suspension obtained was stirred at room temperature for 1 hour. Subsequently, the solid formed was filtered off under suction and washed with 100 ml of methylene chloride. The yellow coloured filtrate was then washed twice with in each case 200 ml of water and twice with 200 ml of saturated sodium chloride solution. The wash solutions were extracted with 500 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and thereafter evaporated under reduced pressure. For purification, the yellowish crude product obtained (15.3 g) was chromatographed on 1.3 kg of silica gel using a 4:1 mixture of ethyl acetate and hexane as the eluent. There were obtained 13.6 g of (S)-α-[[[(1-methyl-1-(morpholinocarbonyl)ethyl]sulfonyl]methyl]hydrocinnamamide as a colourless powder, MS: 383 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:12][C:13](=[O:14])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH:6]3[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.BrC1C=C2C3=C(NC(=O)N3C(C3C=CC=CC=3)CC2)C=1.[CH3:41][C:42]1[C:46](B(O)O)=[C:45]([CH3:50])[O:44][N:43]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O>[CH3:41][C:42]1[C:46]([C:2]2[CH:11]=[CH:10][C:9]3[NH:12][C:13](=[O:14])[N:7]4[C:8]=3[C:3]=2[CH2:4][CH2:5][CH:6]4[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:45]([CH3:50])[O:44][N:43]=1
Reactant: O=c1[nH]c2ccc(Br)c3c2n1C(c1ccccc1)CC3
Reactant: Cc1noc(C)c1B(O)O
Agent: O=C([O-])[O-]
Agent: O=c1[nH]c2cc(Br)cc3c2n1C(c1ccccc1)CC3
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1CCC3c1ccccc1
Temperature: 90 °C
Yield: 56.1 %

Procedure:
A mixture of 7-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (0.050 g, 0.15 mmol) (4.4:1 mixture of isomers with 8-bromo-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one as the minor isomer), (3,5-dimethylisoxazol-4-yl)boronic acid (10.7 mg, 0.0759 mmol), and cesium carbonate (99.0 mg, 0.304 mmol) in 1,2-dimethoxyethane (1.21 mL) and water (0.303 mL) was degassed with nitrogen for 5 min. The reaction mixture was treated with PEPPSI-IPr (5.2 mg, 0.0076 mmol) [Aldrich, cat. #669032], degassed with nitrogen for 5 min, and heated at 90° C. for 1 h. The reaction mixture was then diluted with ethyl acetate (25 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude residue. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (14.7 mg, 28%) as a racemic mixture. 1H NMR (500 MHz, CDCl3) δ 10.00 (s, 1H), 7.34-7.20 (m, 3H), 7.08-6.95 (m, 3H), 6.88-6.76 (m, 1H), 5.54 (s, 1H), 2.45-1.96 (m, 10H); LCMS calculated for C21H20N3O2 (M+H)+: m/z=346.2. found: 346.1.
Reaction SMILES: [I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:13]([O:32][CH2:33][CH2:34][CH2:35][OH:36])(=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[C:10]([I:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:36][CH2:35][CH2:34][CH2:33][O:32][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:5]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO
Reactant: O=C(Cl)c1cc(I)cc(I)c1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCOC(=O)c1cc(I)cc(I)c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,3,5-Triiodobenzoyl chloride (1.54 g, 3.08 mmol) was added to a mixture of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 2.97 mmol) and triethylamine (1 ml) in methylene chloride (80 ml) and the resulting mixture stirred overnight at room temperature under nitrogen. The mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane) to yield 1-(2,3,5-triiodobenzoyloxy)-3-(z,z,z-octadeca-6,9,12-trienoyloxy)propane.
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11](=[O:15])[CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1.[F:16][B-](F)(F)F.N#[O+].ClC1C=CC=CC=1Cl>C(Cl)Cl>[Cl:14][CH2:13][CH2:12][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:16])[CH:10]=2)[CH2:6][CH2:7]1)=[O:15]
Reactant: Nc1ccc2c(c1)N(C(=O)CCCl)CC2
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: O=C(CCCl)N1CCc2ccc(F)cc21
Temperature: 10 °C
Yield: 19.5 %

Procedure:
260 mg (2.2 mmol) of 6-amino-1-(3-chloropropionyl)indoline (prepared as described in Preparation 6) were dissolved in 10 ml of methylene chloride, and 450 mg (2.0 mmol) of nitrosonium tetrafluoroborate were added to the resulting solution while ice-cooling so that the internal temperature was maintained at 10° C. or lower. The mixture was then stirred while ice-cooling for 30 minutes. At the end of this time, 10 ml of 1,2-dichlorobenzene were added to the mixture, and the mixture was stirred at 90° C. for 1 hour. The solvent was then removed from the reaction mixture by distillation under reduced pressure and the resulting residue was purified by silica gel column chromatography, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 97 mg (0.39 mmol) of the title compound as crystals (yield: 20%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13](=[O:18])[C@H:14]([CH2:16][OH:17])[NH2:15].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:18])[C@H:14]([CH2:16][OH:17])[NH:15][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CO)NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A solution of benzoyl chloride (17 g) in ethyl acetate (40 ml) is added dropwise, with stirring, in an ice-cold mixture of L-serine methyl ester, hydrochloride (15.5 g), water (100 ml), sodium bicarbonate (21.8 g), and ethyl acetate (100 ml). After stirring for 2 hours, the organic phase is separated, dried over sodium sulfate, and evaporated to give crystalline N-benzoyl-L-serine methyl ester (22.0 g).
Reaction SMILES: [NH2:1][C@H:2]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([CH2:27][CH3:28])[CH:20]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].C(Cl)Cl.[NH:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[NH:40][C:39]2=[O:49])[CH2:34][CH2:33]1>C(#N)C>[CH2:27]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[CH2:25][CH3:26])[CH2:18][C@@H:2]([NH:1]/[C:35](=[N:38]/[C:39]#[N:40])/[N:32]1[CH2:33][CH2:34][CH:35]([N:38]2[CH2:44][CH2:43][C:42]3[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=3[NH:40][C:39]2=[O:49])[CH2:36][CH2:37]1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4])[CH3:28]
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: CC#N
Solvent: ClCCl
Product: CCc1ccc(C[C@@H](N/C(=N/C#N)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 390 mg (1.01 mmol) (R)-2-amino-3-(3,4-diethyl-phenyl)-1-[4-(1-methylpiperidin-4-yl)-piperazin-1-yl]-propan-1-one, 270 mg (1.01 mmol) diphenylcyano-carbonimidate and 50 mL DCM was stirred for 4 h at RT and then evaporated down under reduced pressure. The residue was combined with 30 mL acetonitrile and 270 mg (1.10 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and refluxed for 14 h. The reaction mixture was evaporated down under reduced pressure and the residue was purified by chromatography. The product fractions were evaporated down, the residue was triturated with PE and suction filtered.
Reaction SMILES: O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:21]([CH2:24][CH2:25][C:26]1[S:30][C:29]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[CH:28][CH:27]=1)=[N+]=[N-]>C1COCC1>[NH2:21][CH2:24][CH2:25][C:26]1[S:30][C:29]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])=[CH:28][CH:27]=1
Reactant: CC(C)OC(=O)c1ccc(CCN=[N+]=[N-])s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ccc(CCN)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Water (0.1 mL) and triphenylphosphine (288 mg, 1.1 mmol) were added sequentially to a solution of the azide from step 3 (239 mg, 1.0 mmol) in THF (2.0 mL) and the reaction was stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and then 1.0 N aqueous HCl (7.5 mL) was added. The mixture was extracted with EtOAc (2×5 mL). The aqueous phase was basified with 2.0 M aqueous NaOH (5 mL). The mixture was extracted with EtOAc (3×10 mL) and these extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford 175 mg (82%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>N1C=CC=CC=1>[CH:16]1([C:19]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:14][CH:15]=2)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1ccc(OC(=O)C2CC2)cc1

Procedure:
Prepared from 6.0 g of 4-hydroxybenzophenone and 4.1 ml of cyclopropanecarbonyl chloride in 70 ml of pyridine. Recrystallized from ethyl acetate-ethanol-water mixture; M.P.~81°-81.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][SH:17])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:28]([S:31][CH2:32][CH:33]([CH3:37])[C:34](Cl)=[O:35])(=[O:30])[CH3:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]([C:14](=[O:19])[CH:15]([CH3:18])[CH2:16][S:17][C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][S:31][C:28](=[O:30])[CH3:29])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(CS)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 8 h

Procedure:
To a mixture of 3 g (0.01M) of N-(3-mercapto-2-methyl propanoyl)-N-cyclopentyl glycine-t-butyl ester, 1.2 g (0.012M) triethylamine in 100 ml methylene chloride was added a solution of 1.8 g (0.01M) of 3-acetylthio-2-methyl propanoyl chloride and stirring continued for 8 hours. It was then washed with water, dried over MgSO4 and evaporated to dryness leaving an oily residue which was purified by HPLC using ethyl acetate--hexane (1:3) as eluent.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>N1C=CC=CC=1.C(N(CC)CC)C>[S:18]1[C:19]2=[N:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21]([OH:22])=[N:15]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccnc1S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Oc1nsc2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diphenylphosphoryl azide (6.9 ml, 32 mmol) in pyridine (50 ml) and triethylamine (4.5 ml) is added, at 0° C., 2-mercaptonicotinic acid (5 g, 32 mmol) in portions. After 30 min, the ice cooling is removed and the mixture is stirred at 25° C. for a further 16 h. The solvent is distilled off under reduced pressure and the residue, a viscous oil, is admixed with methyl tert-butyl ether. While stirring, EtOAc/H2O is added and the mixture is stirred for another 15 min. The resulting pale yellow solid is filtered off with suction and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([F:36])[CH2:13][CH2:14][C:15]1([C:32]([O:34]C)=[O:33])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:37][CH3:38])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([F:36])[CH2:13][CH2:14][C:15]1([C:32]([OH:34])=[O:33])[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[CH2:19][CH2:20]1)=[CH:9][C:8]([O:37][CH3:38])=[CH:7][CH:6]=2
Reactant: COC(=O)C1(CCC(F)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCSc2cc(F)ccc2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(Cl)c(C(F)CCC3(C(=O)O)CCN(CCSc4cc(F)ccc4F)CC3)c2c1
Temperature: 70 °C
Yield: 58.6 %

Procedure:
A mixture of 0.07 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 0.9 cm3 of aqueous 5N sodium hydroxide solution was maintained at a temperature in the region of 70° C. for 4 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue was chromatographed under atmospheric pressure, on a column of silica gel (particle size 70-200μ; mass 10 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume). Fractions 10 to 15 were combined and then concentrated to dryness under the same conditions as above. 0.04 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]-piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:13]=[C:12]([NH:25][C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[N:11]=1>>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([NH:25][C:12]2[N:11]=[C:10]([N:9]=[CH:3][N:4]([CH3:6])[CH3:5])[CH:15]=[C:14]([CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=2)=[CH:27][CH:28]=1)#[N:31]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cc3c(Cl)cccc3Cl)n2)cc1
Product: CN(C)C=Nc1cc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.1 %

Procedure:
1,1-Dimethoxy-N,N-dimethylmethanamine (0.152 mol) was added to 4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-2-pyrimidinyl]amino]benzonitrile (0.0008 mol). The mixture was stirred at room temperature for 2 days and then concentrated. The crude product was purified by trash chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The desired fraction was collected and the solvent was evaporated. The resulting residue was triturated with hexane, yielding 0.15 g (42%) of N′-[2-[(4-cyano-phenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-4-pyrimidinyl]-N,N-dimethyl-methanimidamide (comp. 26; mp. 175-180° C.).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[I:22])[C:16]([OH:18])=[O:17].O>CO>[OH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[I:22])[C:16]([O:18][CH3:1])=[O:17]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(I)c(O)c1
Temperature: 70 °C
Yield: 377.8 %

Procedure:
6.1 g (35.6 mmol) of paratoluene sulfonic acid is added to a solution of 47 g (150 mmol) of 3-hydroxy-4-iodobenzoic acid in 300 ml of methanol. The reaction mixture is heated at 70° C. for 48 hours. After adding 1000 ml of water, the precipitate is filtered, and rinsed with water to neutral pH. 37.4 g (76%) of methyl 3-hydroxy-4-iodobenzoate is obtained in the form of a beige powder.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1>[CH3:23][S:24]([O:1][CH2:2][CH:3]([NH:5][C:6]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[CH3:4])(=[O:26])=[O:25]
Reactant: CC(CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.6 %

Procedure:
In tetrahydrofuran (400 ml) were dissolved 46.5 g (222 mmol) of benzyl (2-hydroxy-1-methylethyl)carbamate and 26.96 g (266 mmol) of triethylamine, and a solution of 27.96 g (244 mmol) of methanesulfonyl chloride in tetrahydrofuran was slowly dropped thereinto at 0° C. After the resulting mixture was stirred at room temperature for 5 hours, the triethylamine hydrochloride precipitated was filtered under reduced pressure and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and water was added thereto, followed by three runs of extraction with ethyl acetate. The extract solution was washed with saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off and the crude crystals thus obtained were washed twice with a solvent (hexane:ethyl acetate=4:1) to obtain 49.5 g (yield 78%) of 2-(benzyloxycarbonylamino)propyl methanesulfonate.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(NC1C2C(=CC=CC=2)CCC1)(=[O:18])C>>[C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCCCC2
Reactant: CC(=O)NC1CCCc2ccccc21
Product: CC(=O)Nc1cccc2c1C(=O)CCCC2

Procedure:
The reaction was carried out in the same manner as in -Example 1-(1), except that 200 mg of the compound prepared in (1) above was used instead of 1-acetylaminotetraline of Example 1-(1). The reaction product was post-treated to produce 55 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[F:11][C:4]1[CH:3]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:9]=[C:8]([F:10])[C:5]=1[CH:6]=[O:7]
Reactant: C=CC(=O)OC
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Temperature: 80 °C
Yield: 86.6 %

Procedure:
4-Bromo-2,6-difluorobenzaldehyde (9.99 g, 45.20 mmol) and methyl acrylate (6.14 ml, 67.81 mmol) were taken up in thoroughly degassed DMA (100 ml) and tri-o-tolylphosphine (1.376 g, 4.52 mmol), palladium(II) acetate (0.507 g. 2.26 mmol) and triethylamine (12.60 ml, 90.41 mmol) added. The reaction was stirred and heated to 80° C. for 6 hours. The reaction mixture was cooled and filtered through a layer of celite, and washed with methanol (50 ml). The crude product was pre-absorbed onto silica and purified by suction chromatography eluting with 0-10% diethyl ether/dichloromethane. Fractions containing the desired product were evaporated and triturated with diethyl ether (50 ml) to afford a yellow solid which was triturated with water (50 ml) and dried under high vacuum at 50° C. to afford (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (8.85 g, 87%) as a yellow solid. 1H NMR (400 MHz, DMSO, 27° C.) δ 3.75 (3H, s), 6.93 (1H, d), 7.52-7.81 (3H, m), 10.18 (1H, s). No mass ion observed in LCMS.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:14]CC1C=CC(C(O)=O)=CC=1>>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccc(CCBr)cc1
Reactant: O=C(O)Cc1cccc(CBr)c1
Product: COC(=O)Cc1cccc(CBr)c1

Procedure:
According to the procedures described in the synthesis method of Intermediate ia-01, 2-[3-(bromomethyl)phenyl]acetic acid (500 mg) synthesized according to the procedures described in International Patent Publication WO00/03980 was used instead of 4-(2-bromoethyl)benzoic acid, and the material was reacted and treated to obtain the title compound (Intermediate il-01, 471 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:16])=[O:15])=[N:11][N:10]=2)=[N:6][CH:7]=1.[OH:24]OS([O-])=O.[K+]>CO.O.O>[Br:1][C:2]1[C:3]([NH:17][C@H:18]([CH:21]([CH3:23])[CH3:22])[CH2:19][OH:20])=[N:4][C:5]([NH:8][C:9]2[NH:13][C:12]([S:14]([CH3:16])(=[O:24])=[O:15])=[N:11][N:10]=2)=[N:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)=O)[nH]2)ncc1Br
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)[C@H](CO)Nc1nc(Nc2nnc(S(C)(=O)=O)[nH]2)ncc1Br

Procedure:
35 mg (0.086 mmol) of (R)-2-[5-bromo-2-(5-methanesulfinyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is dissolved in 4 ml of MeOH/water (4:1) and stirred with 25 mg of oxone (0.25 mmol) at room temperature. The batch is diluted with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation, and the residue is digested with ethyl acetate. 19 mg (0.045 mmol, 52% of theory) of the product (R)-2-[5-bromo-2-(5-methanesulfonyl-4H-[1,2,4]triazol-3-ylamino)-pyrimidin-4-ylamino]-3-methyl-butan-1-ol is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:28])[C:26]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]3[CH:23]=2)=[CH:10][CH:9]=1)=[O:6].Cl.[CH3:30][NH:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:30][N:31]([CH3:32])[C:26]1[C:25]([F:28])=[CH:24][C:4]([C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]4[CH:23]=3)=[CH:12][CH:13]=2)=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccc2nc(-c3ccc(NC(=O)c4cc(F)c(F)c(F)c4)cc3)cn2c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4cc(F)c(N(C)C)c(F)c4)cc3)cn2c1
Temperature: 120 °C
Yield: 79.5 %

Procedure:
A stirred mixture of 3,4,5-trifluoro-N-[4-(6-methylimidazo[1,2-a]pyridin-2-yl)phenyl]benzamide (0.10 g, 0.26 mmol), dimethylamine hydrochloride (0.087 g, 1.07 mmol) and potassium carbonate (0.147 g, 1.07 mmol) in dry DMSO (3 ml) was heated at 120° C. for 22.5 h. After cooling to room temperature, the reaction mixture was added to water (100 ml) and the precipitate was collected by vacuum filtration, and washed with water (40 ml). The solid was dried in an oven at 95° C., and then purified by flash chromatography (25:1 DCM/MeOH) to give the title compound (0.084 g, 80%) as a colourless solid.