Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].ClCCl>C(O)C>[CH:3]([N:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: CC(C)N1CCN(CCCN)CC1
Reaction time: 0.17 h

Procedure:
Hydrazine (8.63 g, 270 mmol) is added to a stirred suspension of 2-[3-(4-isopropylpiperazin-1-yl)-propyl]-isoindole-1,3-dione (17.0 g, 53.9 mmol) in anhydrous ethanol (400 mL). The resultant mixture is heated in an oil bath at 75° C. for 16 hours. At ambient temperature, dichloromethane (300 mL) is added to the mixture and the suspension is allowed to stir for 10 minutes. After filtration and concentration, the title compound is obtained as a tan oil (8.12 g, 81% yield).
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20]([O:22]CC)=[O:21])=[N:16][N:15]4[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[N:16][N:15]4[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Example 4 (260 mg, 0.63 mmol) in methanol (1.5 mL) was added aqueous sodium hydroxide (3N, 0.63 mL, 1.89 mmol, 3.0 eq), and the resulting mixture was stirred at 50° C. for 1 h. The resulting mixture was added to ice water, made slightly acidic with aqueous citric acid (10%), and washed with DCM (3×25 mL). The aqueous phase was made alkaline and adjusted to pH4 using hydrochloric acid (1N). The precipitate was collected by filtration, washed with water and dried under high vacuum overnight to yield 218 mg (88% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([N:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[O:21])=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)N(C)C(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)N(C)C(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-1-isopropyl-1-methyl-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: N.C(OC[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([O:29][CH3:30])=[CH:16][C:17]=2[O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[N:12]=[CH:11]1)(=O)C(C)(C)C>CO>[CH3:30][O:29][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[NH:10][CH:11]=[N:12]2)=[C:17]([O:21][CH:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[CH:16]=1
Reactant: COc1cc(OC2CCN(C)CC2)c2c(=O)n(COC(=O)C(C)(C)C)cnc2c1
Agent: N
Solvent: CO
Product: COc1cc(OC2CCN(C)CC2)c2c(=O)[nH]cnc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.1 %

Procedure:
7.0 N ammonia in methanol (25 ml) was added to (7-methoxy-5-((1-methylpiperidin-4-yl)oxy)-4-oxoquinazolin-3(4H)-yl)methyl pivalate (370 mg, 0.92 mmol) and the solution stirred at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo to give an oil which was triturated with diethyl ether to give an orange solid which was collected by suction filtration and dried in vacuo to yield 7-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one (200 mg, 75% yield):
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][C@@H:21]1[CH2:27][CH3:28])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O[N:30]1[C:34](=[O:35])[C:33]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]2[C:31]1=[O:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[C:13]([N:20]1[CH2:25][CH2:24][C@@H:23]([O:26][N:30]2[C:34](=[O:35])[C:33]3[C:32](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]2=[O:40])[CH2:22][C@@H:21]1[CH2:27][CH3:28])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC[C@H]1C[C@H](ON2C(=O)c3ccccc3C2=O)CCN1C(=O)OC(C)(C)C

Procedure:
With stirring and under nitrogen, a solution of 0.283 ml (0.001693 mol) of diethyl azodicarboxylate (93%) in 1 ml of benzene is added dropwise at 20°-30° C. to a suspension of 0.37 g (0.001613 mol) of cis-N-BOC-2-ethyl-4-hydroxypiperidine, 0.263 g (0.001613 mol) of N-hydroxyphthalimide and 0.423 g (0.001613 mol) of triphenylphosphine in 5 ml of benzene. The reaction mixture is further stirred for 15 hours at room temperature, then filtered to remove precipitated diethyl 1,2-hydrazinedicarboxylate, and the filtrate is concentrated under vacuum. The residue is purified by flash chromatography over silica gel using ethyl acetate:hexane (1:3), to give the title compound as a colourless resin; Rf =0.66 (silica gel/ethyl acetate:hexane (2:1)).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14](=[O:22])(=[O:21])[NH:13]2)[CH2:9]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH:8]1[CH2:12][CH2:11][C:10]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14](=[O:22])(=[O:21])[NH:13]2)[CH2:9]1
Reactant: O=S1(=O)NC2(CCN(Cc3ccccc3)C2)c2ccccc21
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: O=S1(=O)NC2(CCNC2)c2ccccc21
Yield: 41.3 %

Procedure:
To a solution of 1′-benzylspiro[1,2-benzisothiazole-3,3′-pyrrolidine]1,1-dioxide (170 mg, 0.00054 mol) in methanol were added Pd black (150 mg) and formic acid (0.2 mL, 0.005 mol). The resulting reaction mixture was refluxed overnight, then cooled to r.m., and then filtered and concentrated to give the desired compound (50 mg, 42% Yield). MS (ESI): 225.1 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)[CH:6]=1)[CH3:2]>C(O)C.CN(C=O)C.[Pd]>[CH2:1]([NH:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4=CCNCC4)n[nH]c3c2)c1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4CCNCC4)n[nH]c3c2)c1
Yield: 58 %

Procedure:
A solution of N-ethyl-4-methyl-3-[3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indazol-6-yl]benzamide (Intermediate 15, 360 mg) in ethanol (10 ml) and DMF (3 ml) was stirred with 10% palladium on carbon (50 mg) under an atmosphere of hydrogen for 24 h. The catalyst was removed by filtration, the solvent was evaporated and the residue was dissolved in methanol and applied to an SCX ion exchange cartridge. The cartridge was eluted with a solution of aqueous ammonia (0.88) in methanol (10%) and the resultant product was further purified on a column of silica, eluting with a dichloromethane/methanol gradient, to give the title compound (210 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][N:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.CCOC(C)=O>[CH2:1]([O:3][C:4]([CH:6]1[CH:11]([NH2:29])[CH2:10][CH2:9][N:8]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(c2ccc(OC)c(OC)c2)CCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CN(c2ccc(OC)c(OC)c2)CCC1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.1 %

Procedure:
A suspension of rac-1-(3,4-dimethoxy-phenyl)-4-oxo-piperidine-3-carboxylic acid ethyl ester (640 mg) and ammonium acetate (3 g) in 10 ml methanol was stirred 18 h at RT., then sodium cyanoborohydride (2 g) was added. After 18 h at RT, the mixture was diluted with AcOEt, washed twice with water and brine. The organic layers were dried over MgSO4, filtered, evaporated and chromatographied (silica gel, AcOEt/heptane, 1/1) to give the title compound (450 mg, 70%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C1COCC1.[OH:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:28][CH2:29][N:30]1[CH:35]=[CH:34][C:33]2[CH:36]=[CH:37][O:38][C:32]=2[C:31]1=[O:39])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl.O>[CH3:1][S:2]([O:11][CH2:12][CH2:13][CH2:14][N:15]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])[CH2:28][CH2:29][N:30]1[CH:35]=[CH:34][C:33]2[CH:36]=[CH:37][O:38][C:32]=2[C:31]1=[O:39])(=[O:4])=[O:3]
Reactant: O=c1c2occc2ccn1CCN(CCCO)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCN(CCn1ccc2ccoc2c1=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
Methanesulfonyl chloride (0.14 ml, 1.8 mmol) was added to a THF solution (30 ml) of N-(3-hydroxypropyl)-2-nitro-N-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]benzenesulfonamide (644 mg, 1.5 mmol) and triethylamine (0.34 ml, 2.3 mmol), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→0:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 480 mg (yield: 64%) of 3-{(2-nitrobenzenesulfonyl)-[2-(7-oxo-7H-furo[2,3-c]pyridin-6-yl)ethyl]amino}propyl methanesulfonate as a white amorphous solid.
Reaction SMILES: C1C2C=CC=CC=2CCNC1.C(N1CCC2C=CC(S([Cl:29])(=O)=O)=CC=2CC1)(=O)C.C([N:33]1[CH2:39][CH2:38][C:37]2[CH:40]=[CH:41][C:42]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:43][C:36]=2[CH2:35][CH2:34]1)(=O)C.Cl>>[ClH:29].[CH3:47][S:44]([C:42]1[CH:41]=[CH:40][C:37]2[CH2:38][CH2:39][NH:33][CH2:34][CH2:35][C:36]=2[CH:43]=1)(=[O:46])=[O:45]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Reactant: CC(=O)N1CCc2ccc(S(C)(=O)=O)cc2CC1
Agent: Cl
Agent: c1ccc2c(c1)CCNCC2
Product: CS(=O)(=O)c1ccc2c(c1)CCNCC2

Procedure:
Following the procedure of Examples 1 and 4, 2,3,4,5-tetrahydro-1H-3-benzazepine was converted to 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine and then to 3-acetyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine which was hydrolyzed with hydrochloric acid to give 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, m.p. 275°-277° C.
Reaction SMILES: C[C@@H]1CN(CC2C=NC(C)=NC=2)C[C@H]1C1NC(=O)C2C=NN(C3CCOCC3)C=2N=1.Cl.[CH2:32]([C@@H:34]1[CH2:38][NH:37][CH2:36][C@H:35]1[C:39]1[NH:40][C:41](=[O:54])[C:42]2[CH:47]=[N:46][N:45]([CH:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[C:43]=2[N:44]=1)[CH3:33].C([BH3-])#N.[Na+].[CH3:59][O:60][C:61]1[CH:68]=[CH:67][C:64]([CH:65]=O)=[CH:63][N:62]=1>>[CH2:32]([C@@H:34]1[CH2:38][N:37]([CH2:65][C:64]2[CH:63]=[N:62][C:61]([O:60][CH3:59])=[CH:68][CH:67]=2)[CH2:36][C@H:35]1[C:39]1[NH:40][C:41](=[O:54])[C:42]2[CH:47]=[N:46][N:45]([CH:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)[C:43]=2[N:44]=1)[CH3:33]
Reactant: COc1ccc(C=O)cn1
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: Cl
Agent: [BH3-]C#N
Product: CC[C@@H]1CN(Cc2ccc(OC)nc2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride, sodium cyanoborohydride and 6-methoxynicotinaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.04 (d, J=2.1 Hz, 1H), 8.02 (s, 1H), 7.73-7.71 (m, 1H), 6.78 (d, J=8.7 Hz, 1H), 4.80-4.75 (m, 1H), 4.12-4.10 (m, 2H), 3.92-3.90 (m, 3H), 3.72-3.70 (m, 1H), 3.61-3.54 (m, 3H), 3.32 (t, J=8.3 Hz, 1H), 2.99 (m, 1H), 2.91 (m, 1H), 2.41 (m, 1H), 2.40-2.28 (m, 2H), 2.21 (m, 1H), 1.95 (m, 1H), 1.91-1.83 (m, 2H), 1.65-1.45 (m, 2H), 0.92 (t, J=7.5 Hz, 3H). MS: (M+H m/z 439.2).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:9]([C:12]1[C:17](Cl)=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>>[N+:9]([C:12]1[C:17]([O:7][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[CH3:8])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(Oc2ccccc2C)c1[N+](=O)[O-]

Procedure:
A mixture of o-cresol (4.9 g.), ethyl 2-(2-nitro-3-chlorophenyl)acetate (10.0 g.), potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give the captioned compound (3.4 g.). bp 173° to 176° C./0.2 to 0.4 mmHg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[C:4](Cl)[N:3]=1.[CH3:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH2:20])=[O:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:10][NH:11][C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]1[NH:20][C:4]1[C:5]([Cl:8])=[CH:6][N:7]=[C:2]([Cl:1])[N:3]=1)=[O:13]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)[C@@H]1CCCC[C@@H]1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H]1CCCC[C@@H]1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.8 %

Procedure:
2,5,6-trichloropyrimidine (368 mg, 2.0 mmol), cis-2-amino-cyclohexanecarboxylic acid methylamide (308 mg, 2.0 mmol), and N,N-diisopropylethylamine (387 mg, 3.0 mmol) were combined in 10 mL isopropyl alcohol and stirred at room temperature for 24 hours. The reaction was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated and was dried (sodium sulfate) to afford a solid which was purified on silica gel (1% to 3% methanol:dichloromethane gradient elution) to afford 502 mg (83%) of cis-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methylamide as a white foam. Mp: 108° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:8]([S:9][CH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: SCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CSCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a solution of phenylethyl mercaptan (0.66 g, 4.80 mmol) and methyl 3-(bromomethyl)benzoate (1.0 g, 4.37 mmol) in DMF (10 mL) was added Cs2CO3 (2.84 g, 8.73 mmol). The suspension was stirred at rt for 3 h. The reaction mixture was then diluted with ethyl acetate and water. The organic layer was separated, washed with brine three times, dried over MgSO4. The filtrate was concentrated in vacuo to give a light yellow oil. The crude product was purified by flash chromatography on silica gel eluting with 30% ethyl acetate in hexane to give the desired product (1.2 g, 96%) as a colorless oil. 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.96-7.94 (m, 1H), 7.55-7.53 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.33-7.28 (m, 2H), 7.25-7.17 (m, 3H), 3.95 (s, 3H), 3.76 (s, 2H), 2.89-2.85 (m, 2H), 2.69-2.65 (m, 2H). MS (ESI): 287.1 (M+H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.O.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[C:24]([C:26](Cl)=[O:27])=[N:23][C:22]([C@@H:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]3[C:33]=1[N:34]=[CH:35][N:36]3[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH3:30])=[CH:21]2>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[C:24]([C:26]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:27])=[N:23][C:22]([C@@H:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]3[C:33]=1[N:34]=[CH:35][N:36]3[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[CH3:30])=[CH:21]2
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)Cl)n4)ncnc32)cc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C(=O)N5CCOCC5)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of morpholine (34 mg, 0.392 mmol, 1.3 eq) and triethylamine (100 mg, 0.981 mol, 3 eq) in DCM (20 mL), (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbonyl chloride 11 was added at RT. The resulting mixture was stirred at RT for 1 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl) (morpholino)methanone 12.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=3[F:31])=[CH:16][C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCOCC1.[OH-].[Pd+2].[OH-]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:15]2[C:12]3[C:13](=[O:14])[NH:8][CH:9]=[N:10][C:11]=3[N:18]([CH3:19])[C:17](=[O:20])[CH:16]=2)=[C:23]([F:31])[CH:24]=1
Reactant: Cn1c(=O)cc(Nc2ccc([N+](=O)[O-])cc2F)c2c(=O)n(Cc3ccccc3)cnc21
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: Cn1c(=O)cc(Nc2ccc(N)cc2F)c2c(=O)[nH]cnc21
Yield: 66.4 %

Procedure:
3-Benzyl-5-(2-fluoro-4-nitrophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (900 mg, 2.1 mmol), palladium hydroxide (20% on carbon, 500 mg) and ammonium formate (500 mg, 7.9 3 mmol, 3.7 eq) were stirred in dioxane (10 mL) at 90° C. for 4 hours. The suspension was filtered and the solid refluxed in DMF (20 mL) for 1 hour then filtered. This was repeated 3 times. The filtrates were combined and evaporated to give 420 mg of title compound as a white solid (65%). 1H NMR (400 MHz, MeOD) δ ppm 3.56 (br. s., 3 H) 5.38 (s, 1 H) 6.51 (s, 1 H) 6.54 (t, J=1.89 Hz, 1 H) 7.07 (t, J=8.46 Hz, 1 H) 8.17 (s, 1 H) [M+H] calc'd for C14H12FN5O2, 302; found, 302.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:26]=[CH:25][CH:24]=[CH:23][C:14]=1[O:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C.O>[Br:1][C:18]1[N:17]=[C:16]([O:15][C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[C:9]([CH3:12])([CH3:10])[CH3:11])[C:21]([NH2:22])=[CH:20][CH:19]=1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1nc(Br)ccc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 104.3 %

Procedure:
A solution of N-bromosuccinimide (2.32 g, 13.0 mmol) in DMF (20 ml) was added to a cold (−20° C.) solution of 1b (2.76 g, 11.4 mmol) in DMF (25 ml). The reaction rapidly turned dark red. HPLC analysis after 5 min showed that the reaction was complete. The reaction was quenched with a freshly prepared solution of sodium thiosulfate (40 ml, 10% aqueous). A precipitate formed. The mixture was warmed to rt and was diluted with water (60 ml). The solid was filtered, washed with water and dried overnight under reduced pressure to give 123a (3.82 g, 96% yield) as brown solid. [M+H]+=321.14. 1H NMR (500 MHz, CDCl3) δ ppm 1.40 (s, 9H), 3.91 (s, 2H), 6.93 (m, 2H), 7.00 (d, J=8.07 Hz, 1H), 7.12 (t, J=7.73 Hz, 1H), 7.20 (t, J=7.73 Hz, 1H), 7.41 (d, J=8.07 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([NH:21][C:22](=[O:24])C)[CH:19]=[CH:20][C:13]=2[NH:12][C:11](=[O:25])[CH2:10]1.CO.O=S(Cl)Cl.[CH2:33]([N:40]=C=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CO.Cl>[CH2:33]([NH:40][C:22](=[O:24])[NH:21][C:18]1[CH:19]=[CH:20][C:13]2[NH:12][C:11](=[O:25])[CH2:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:2])=[O:26])[C:15](=[O:16])[C:14]=2[CH:17]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)CCCCCN1CC(=O)Nc2ccc(NC(C)=O)cc2C1=O
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Product: O=C(O)CCCCCN1CC(=O)Nc2ccc(NC(=O)NCc3ccccc3)cc2C1=O
Reaction time: 18 h
Yield: 19.5 %

Procedure:
80 mg (0.22 mmol) 6-(7-acetylamino-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-hexanoic acid methyl ester was dissolved in 1 ml MeOH/HCl (freshly prepared from 10 ml MeOH and 1 ml SOCl2). The solution was stirred for 18 h and concentrated in vacuo. The residue was taken up in 2 ml of THF/MeOH (1: 1) and 0.5 ml 1N aqueous NaOH was added. After stirring for 16 h at 22° C. the mixture was neutralised by addition of solid carbon dioxide, and the solvents were evaporated. The residue was taken up in DMF (2.5 ml) and 0.032 ml benzylisocyanate (0.26 mmol) was added. The mixture was shaken at 45° C. over night and evaporated. The crude product was purified by preparative HPLC to give 6-[7-(3-benzyl-ureido) -2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl]-hexanoic acid (19 mg, 0.043 mmol): MS (ISN) 437(M−H)−.
Reaction SMILES: [CH:1]([N:4]=C=NC(C)C)(C)C.OC(C(F)(F)F)=O.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][CH:34]=2)=[O:31])[CH:26]([CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.CN.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[CH3:1][NH:4][C:37]([C:36]1[CH:40]=[CH:41][C:33]([NH:32][C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:23])[CH2:25][CH:26]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:31])=[CH:34][CH:35]=1)=[O:39]
Reactant: CC(C)N=C=NC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(C(=O)O)cc2)C(COc2cccnc2)C1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1ccc(NC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)cc1
Reaction time: 8 h

Procedure:
Diisoproylcarbodiimide (0.037 mL, 0.24 mmol) was added to a solution of 4-(4-(tert-butoxycarbonyl)-2-((pyridin-3-yloxy)methyl)piperazine-1-carboxamido)benzoic acid TFA salt (123 mg, 0.215 mmol), methylamine hydrochloride (16 mg, 0.237 mmol), diisopropylethylamine (0.123 mL, 0.710 mmol), and N-hydroxybenzotriazole (32 mg, 0.237 mmol) in CH2Cl2 (2 mL) and DMF (0.5 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and was purified by HPLC (10 to 90% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 103 mg (82%) of the TFA salt of the title compound as a white solid. LC-MS: RT=5.99 min, [M+H]+=470.2.