Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C2C=NC(N)=NC=2)=CC=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].C(Cl)CCl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[N:35][C:36]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]([OH:50])=O)=[CH:42][CH:41]=3)=[N:37][CH:38]=2)=[CH:29][CH:28]=1.[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.ClCCl.CN1C(=O)CCC1>[CH2:16]([N:18]([CH2:19][CH3:20])[C:48](=[O:50])[CH2:47][CH2:46][C:43]1[CH:42]=[CH:41][C:40]([NH:39][C:36]2[N:37]=[CH:38][C:33]([C:30]3[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)=[CH:34][N:35]=2)=[CH:45][CH:44]=1)[CH3:17]
Reactant: COc1ccc(-c2cnc(Nc3ccc(CCC(=O)O)cc3)nc2)cc1
Reactant: CCNCC
Agent: CN(C)c1ccncc1
Agent: COc1ccc(-c2cnc(N)nc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCCC1=O
Product: CCN(CC)C(=O)CCc1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cc1
Reaction time: 3 h

Procedure:
4-(3-Diethylamino-propyl)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine can be prepared by the following procedure. Diethylamine (10 mmol), EDC (25 mmol) and DMAP (0.1 mmol) are dissolved in dichloromethane (3 mL) and added to the crude 3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionic acid dissolved in NMP (from example 5ao) at rt. After 3 h, sat. aq NH4Cl is added and the mixture is extracted with EtOAc. The combined extracts are dryed over anhydrous Na2SO4 and solvent is removed. Purification by preparative HPLC yields N,N-diethyl-3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=3)[S:10][C:3]=12.[CH:18]1([NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:20][CH2:19]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:18]1([NH:21][C:22]([C:24]2[C:25]3[CH:33]=[CH:32][C:31]([O:34][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]6[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=6)[S:10][C:3]=45)=[CH:30][C:26]=3[S:27][C:28]=2[CH3:29])=[O:23])[CH2:20][CH2:19]1
Reactant: OCc1csc(-c2cc3nccc(Cl)c3s2)n1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nc(CO)cs5)sc34)ccc2c1C(=O)NC1CC1
Yield: 43.6 %

Procedure:
This material was prepared by reacting [2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1,3-thiazol-4-yl]methanol (124 mg, 0.5 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide 8c (113 mg, 0.4 mmole) and Cs2CO3 (391 mg, 1.2 mmole) in a manner similar to that previously described for example 1 to give a yellow solid (86 mg, 44%). 1H NMR (DMSO-d6, 300 MHz) δ 8.56 (1H, d, J=5.4 Hz), 8.46 (1H, d, J=4.3 Hz), 8.17 (1H, s), 7.96 (1H, d, J=2.2 Hz), 7.81 (1H, d, J=8.8 Hz), 7.63 (1H, s), 7.34 (1H, dd, J=2.2, 8.8 Hz), 6.75 (1H, d, J=5.4 Hz), 4.60 (2H, d, J=4.9 Hz), 2.96–2.85 (1H, m), 2.57 (3H, s), 0.78–0.67 (2H, m), 0.62–0.53 (2H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH3:18])(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)co1
Yield: 64.3 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-2-methyl-benzenesulfonamide (7-02) (22.0 g, 64.32%) was synthesized as a light brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (20.5 g, 88.74 mmol) and 2-methyl-benzenesulfonyl chloride (6-02) (20.23 g, 106.49 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[N:21]=3)[C:16](O)=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[O:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][NH2:43])[CH2:37][CH2:36]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[N:21]=3)[C:16]([NH:43][CH2:42][CH2:41][N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[O:17])=[CH:9][CH:8]=2)=[CH:23][CH:24]=1
Reactant: NCCN1CCOCC1
Reactant: Cc1cc(C(=O)O)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCN2CCOCC2)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.2 %

Procedure:
In a 50 mL vial with a screw-top septum 2-(4-(4-fluorophenoxy)phenyl)-6-methylisonicotinic acid (300 mg, 0.9 mmol) was dissolved in DCM (5 mL). To the solution were added 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide (144 mg, 0.9 mmol) and 1-hydroxybenzotriazole (63 mg, 0.46 mmol). The reaction mixture was stirred for 20 minutes at room temperature. Then, 2-morpholinoethanamine (121 mg, 0.9 mmol) was added. The reaction mixture was stirred for 20 hours at room temperature and was then chromatographed directly by combiflash without workup using a 40-gram silica column and a gradient of MeOH (40% max) in chloroform to provide 2-(4-(4-fluorophenoxy)phenyl)-6-methyl-N-(2-morpholinoethyl) isonicotinamide as a clear oil (142 mg). 1H NMR (CD3OD): 8.05-7.99 (m, 2 H), 7.98 7.94 (m, 1 H), 7.56-7.51 (m, 1 H), 7.19-7.03 (s, 6 H), 3.75-3.67 (m, 4 H), 3.62-3.54 (m, 2 H), 2.68-2.60 (m, 5 H), 2.59-2.52 (m, 4 H). LCMS: m/z=436 [M+H+]+.
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[H-].[Na+].[CH2:28](Br)[CH:29]=[CH2:30]>C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:25][CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:30][CH:29]=[CH2:28])[C:15]=2[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: -60 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
Anhydrous DMF solution (10 ml) of 2-t-butoxycarbonyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (4.40 g, 16.2 mmol) was mixed with 60% sodium hydride (700 mg, 10 mmol) and stirred at roam temperature for 1 hour. The reaction solution was cooled to −60° C., mixed with allyl bromide (2.18 g, 18 mmol) and then returned to room temperature by further stirring for 1 hour. The reaction solution was mixed with ethyl acetate (150 ml), washed with water and dried with anhydrous sodium sulfate, and then the solvent was removed by evaporation under a reduced pressure. The thus obtained residue was purified by a silica gel chromatography to obtain 4.32 g of the title compound as an oil (13.8 mmol, 87% in yield).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH3:30][C:31]1([CH3:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][C:31]1([CH3:37])[CH2:36][CH2:35][CH2:34][N:33]([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])[CH2:32]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: CC1(C)CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCCN(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)C1

Procedure:
82 mg (0.20 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 32 mg (0.27 mmol) 3,3-dimethyl-piperidine, 80 μL (0.57 mmol) triethylamine and 70 mg (0.22 mmol) TBTU in 0.80 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=O)=[C:4]([CH2:13]Br)[N:3]=1.[NH2:15][C@@H:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH2:17][OH:18].C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[N:3]=[C:4]2[CH2:13][N:15]([C@@H:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH2:17][OH:18])[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: N[C@H](CO)Cc1cccc(F)c1
Reactant: CCOC(=O)c1ccc(Br)nc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccc(Br)nc2CN1[C@H](CO)Cc1cccc(F)c1
Temperature: 67 °C
Reaction time: 8 h

Procedure:
Ethyl 6-bromo-2-(bromomethyl)nicotinate (0.17 g, 0.53 mmol), (2S)-2-amino-3-(3-fluorophenyl)propan-1-ol (0.11 g, 0.64 mmol), N,N-diisopropylethylamine (0.2 g, 2 mmol) and 1,4-dioxane (5 mL) were mixed in one 20 mL microwave tube, and the mixture was stirred at 67° C. for overnight. LC-MS showed most starting material was converted to Br-replacement product. Then the temperature was raised to 125° C. for 45 mins, cooled to room temperature, then worked up with EtOAc and aqueous NaHCO3 solution, extracted twice with EtOAc and dried over sodium sulfate, and concentrated under reduced pressure. Purification by combi-flash chromatography gave the desired product. LC-MS found: 365.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH:44][NH2:45])(=O)[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1>CC1C=CC(C)=CC=1>[C:29]1([C:19]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]4)=[CH:13][CH:14]=3)=[N:28][C:22]3[O:23][CH2:24][C:25]4[N:26]([C:36]([C:37]5[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=5)=[N:44][N:45]=4)[C:21]=3[CH:20]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccncc3)CO4)cc2)CCC1
Temperature: 150 °C
Yield: 11.9 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.205 mmol) and isonicotinic acid hydrazide (127 mg, 0.923 mmol) in p-xylene (2 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (14 mg, 12%), LCMS (Method A): RT=6.28 min, M+1=573. 1H NMR (500 MHz, CDCl3): 8.90 (2H, d), 7.70 (2H, d), 7.38 (1H, s), 7.36-7.32 (2H, d), 7.31-7.27 (2H, d), 7.25-7.18 (3H, m), 6.98-6.93 (2H, dd), 5.66 (2H, s), 2.55-2.41 (4H, m), 2.14-2.01 (1H, m), 1.88-1.78 (1H, m), 1.46-1.24 (9H, bs).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17].[O:19]=[C:20]1[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([NH:29][CH:30]=[O:31])[CH:26]=2)[NH:21]1>>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[NH:11][C:12]([CH:15]=[C:28]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([NH:29][CH:30]=[O:31])[CH:26]=4)[NH:21][C:20]3=[O:19])=[C:13]([CH3:14])[C:7]=2[C:6]1=[O:17]
Reactant: O=CNc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(NC=O)cc32)[nH]c2c1C(=O)N(CCN(C)C)CC2
Yield: 69.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 112 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-formamide as starting materials to give N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-formamide (43 mg, 69.3%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[Na+].[CH2:21]([OH:23])[CH3:22].NOS(O)(=O)=O>O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1=[N:16][N:17]([N:1]=[CH:2][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:18]=[C:13]1[CH2:12][CH:11]3[CH:21]([C:22]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1)[OH:23])=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Reactant: CCO
Agent: NOS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c2c(nc3ccccc13)C(C(O)c1ccccc1)Cc1cn(N=Cc3ccccc3)nc1-2
Temperature: 25 °C

Procedure:
To a warm suspension (50° C.) of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (26.77 g) and solid sodium hydroxide (24.9 g) in water (377 ml) was added ethanol (1133 ml). Hydroxylamine-o-sulfonic acid (34.27 g) was added in portions over 15 minutes and the reaction was cooled to room temperature. The resulting solid was filtered, washed with water, air dried, heated with excess benzaldehyde, filtered to remove insolubles, concentrated, and triturated (diethyl ether) to yield 10.32 g of a mixture of the target product and 11-amino-2-benzylideneamino-4,5-dihydro-2H-pyrazolo[3,4-a]acridine.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([CH3:23])[C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([CH3:23])[C:14]([CH:21]=[O:29])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.40 g) in a mixed solvent of acetone (8.00 mL)-acetonitrile (8.00 mL)-water (8.00 mL) were added osmium oxide (fixed catalyst I) (0.15 g) and sodium periodate (1.24 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH:16][CH2:17][CH2:18][NH2:19])=[N:13][CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O-:22])=[O:21].C(O)(=O)C.[BH4-].[Na+]>C(OCC)(=O)C.O.C(O)C>[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH:19][CH2:18][CH2:17][NH:16][C:14]1[C:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][S:9][C:10]=2[N:11]=[CH:12][N:13]=1)([O-:22])=[O:21]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NCCNc1ncnc2scc(-c3ccccc3)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(CNCCNc2ncnc3scc(-c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A mixture of N-(5-phenylthieno[2,3-d]pyrimidin-4-yl)ethane-1,2-diamine (Maybridge) (30 mg, 0.11 mmol), 3-nitrobenzaldehyde (18 mg, 0.12 mmol), acetic acid (6 mg, 0.10 mmol) and ethanol (3.0 mL) was stirred at room temperature for 30 minutes, followed by the addition of 7.6 mg (0.20 mmol) of sodium borohydride (7.6 mg, 0.20 mmol). The reaction was stirred for an additional 30 minutes and then water (0.2 mL) and ethyl acetate (20 mL) were added. The mixture was washed with aqueous sodium bicarbonate solution (2×20 mL) and the organic layer was separated, concentrated, and purified by column chromatography over silica gel using a gradient elution from 2.5% to 5% methanol in dichloromethane as eluant to give 34.2 mg (77%) N-(3-nitrobenzyl)-N′-(5-phenylthieno[2,3-d]pyrimidin-4-yl)ethane-1,2-diamine as a colorless gum. MS [M+H] 406.2, 1H NMR (CDCl3) δ (ppm) 8.49 (s, 1H), 8.11 (d, J=6.6 Hz, 1H), 8.06 (s, 1H), 7.50-7.32 (m, 7H), 7.08 (s, 1H), 5.48 (b, 1H), 3.75 (s, 2H), 3.55 (m, 2H), 2.75 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[Si:22]([O:29][CH2:30][C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([Cl:55])[C:48]=1[CH3:56])[C:32]([NH:34][NH:35][C:36](=O)[C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=1)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl>[Si:22]([O:29][CH2:30][C@@H:31]([NH:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[C:49]([Cl:55])[C:48]=1[CH3:56])[C:32]1[O:33][C:36]([C:37]2[CH:38]=[CH:39][C:40]([C:43]#[N:44])=[CH:41][CH:42]=2)=[N:35][N:34]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: Cc1c(N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(N[C@H](CO[Si](C)(C)C(C)(C)C)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Yield: 58.6 %

Procedure:
Polymer supported triphenylphosphine (1.5 g, 4.46 mmol) was diluted in 200 mL of DCM followed by addition of I2 (1.13 g, 4.46 mmol) and TEA (1.67 mL, 18.8 mmol) at 0° C. (R)—N′-(3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)propanoyl)-4-cyanobenzohydrazide (1.52 g, 2.97 mmol) in 200 ml DCM was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred. The temperature was allowed to come to room temperature and stirred for additional 10 min. The reaction was quenched with 50 mL saturated sodium thiosulfate and the biphasic mixture was separated. The aqueous layer was extracted with EtOAc (3×40 mL) and the combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting crude oil was purified by flash chromatography (SiO2) to provide the title compound (0.860 g, 59%). The crude material was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[CH3:31][N:32]([CH3:38])[CH2:33][CH2:34][CH2:35][NH:36][CH3:37]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([N:36]([CH2:35][CH2:34][CH2:33][N:32]([CH3:38])[CH3:31])[CH3:37])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[S:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1
Reactant: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Reactant: CNCCCN(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1N(C)CCCN(C)C
Yield: 66.4 %

Procedure:
Following the procedure used to prepare Example 27, 150 mg (0.34 mmol) of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile is reacted with 238 mg (2.05 mmol) of N, N, N′-trimethyl-1,3-propanediamine in 1 mL of 1-methyl-2-pyrrolidinone at 105° C. for 16 hours to yield 121 mg of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenylamino]-7-{[3-(dimethyl)aminopropyl]-methylamino}-6-methoxyquinoline-3-carbonitrile as a tan solid, mp 196-201° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH2:11]([N:14]=[C:15]=[O:16])[CH:12]=[CH2:13]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH2:11]([NH:14][C:15]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1)=[O:16])[CH:12]=[CH2:13]
Reactant: Oc1ccc(N=C=S)cc1
Reactant: C=CCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCNC(=O)Oc1ccc(N=C=S)cc1

Procedure:
By a procedure similar to that of Example I, the above compound (11.1 g.) in the form of a waxy solid, was prepared from 9.1 g. (0.06 m.) of p-hydroxyphenylisothiocyanate and 5.0 g. (0.06 m.) of allylisocyanate, using 35 mls. of chloroform as a solvent and 3 drops each of triethylamine and dibutyltin dilaurate as catalysts.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:9])[CH2:5][CH:6]([OH:8])[CH3:7].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:8][CH:6]([CH3:7])[CH2:5][CH:4]([CH3:9])[CH3:3])[N:14]=[CH:13][N:12]=1
Reactant: CC(C)CC(C)O
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)CC(C)Oc1cc(Cl)ncn1
Reaction time: 0.17 h

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.23 g of 4-methyl-2-pentanol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 0.3 g of 4,6-dichloropyrimidine in tetrahydrofuran at 0° C., followed by stirring at the same temperature for 2 hours and further stirring at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate to give a crude product of 4-chloro-6-(1,3-dimethylbutoxy)pyrimidine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=O)[CH:12]=2)[C:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:6]1[C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1.[H-].[Na+].[OH2:31]>CN(C)C=O>[CH:18]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:31])=[CH:12][C:13]=3[N:5]3[CH2:4][CH2:3][CH2:2][N:25]4[CH:26]=[CH:27][CH:28]=[C:24]4[C:6]=23)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc[nH]3)n(CCCCl)c2c1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCCn1cccc1-3
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of methyl 1-(3-chloropropyl)-3-cyclohexyl-2-(1H-pyrrol-2-yl)-1H-indole-6-carboxylate (130 mg, 0.326 mmol) in N,N-dimethylformamide (4 ml) was added sodium hydride (17 mg, 0.424 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give methyl 13-cyclohexyl-6,7-dihydro-5H-pyrrolo[2′,1′:3,4][1,4]diazepino[1,2-a]indole-10-carboxylate (91 mg, yield 77%).