Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[C:9](=[O:17])[N:10]([CH3:16])[C:11](=[O:15])[N:12]([CH3:14])[N:13]=1.C(N(CC)CC)C.ClCCl>C1(C)C=CC=CC=1>[CH3:14][N:12]1[C:11](=[O:15])[N:10]([CH3:16])[C:9](=[O:17])[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:13]1
Reactant: C1CNCCN1
Reactant: Cn1nc(Br)c(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cn1nc(N2CCNCC2)c(=O)n(C)c1=O
Temperature: 110 °C
Yield: 79.6 %

Procedure:
4.75 g (55.15 mmol) of piperazine are placed in the presence of 4.05 g (18.4 mmol) of intermediate 1b in toluene at room temperature for 30 min. 2.8 mL (20.1 mmol) of triethylamine are added and the mixture is heated for 18 h at 110° C. After concentration of the reaction medium, the obtained residue is taken up with dichloromethane and washed with water. After drying on MgSO4, the organic phase is dry concentrated. The obtained residue is purified by flash chromatography (CH2Cl2-MeOH: 60-40). 3.3 g of intermediate 12a is obtained as a white powder (yield: 79%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:19]1[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O.[Cu]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:19]2[CH:24]=[CH:23][C:22](=[O:25])[CH:21]=[CH:20]2)=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: O=c1cc[nH]cc1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3nc(-n4ccc(=O)cc4)cnc3N)[nH]c2c1
Yield: 29.5 %

Procedure:
A mixture of 5-bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (80 mg, 0.263 mmol), pyridin-4(1H)-one (287 mg, 2.63 mmol), cesium carbonate (257 mg, 0.8 mmol) and copper (5 mg, 0.08 mmol) were heated in NMP (2 mL) at 150° C. for 1 hour. The reaction mixture was diluted with EtOAc, washed with 1N NaOH, and the organic layer filtered through a pad of celite and concentrated in vacuo. The resulting solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (24.7 mg, 30% Yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluoro-benzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [C:1]([C:6]([OH:8])=[O:7])#[C:2][C:3](O)=[O:4].[CH2:9]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[S:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[CH2:21]([N:20]1[C:3](=[O:4])[C:2](=[CH:1][C:6]([OH:8])=[O:7])[S:19][C:18]1=[N:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCCCNC(=S)NCCCCCCCC
Solvent: CO
Product: CCCCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
A mixture of acetylenedicarboxylic acid (7.2 g, 60 mmoles) and N,N'-dioctylthiourea (18 g, 60 mmoles) in methanol (300 mls) is stirred at room temperature for 16 hours. The solvent is removed under reduced pressure to leave a syrupy residue which eventually crystallizes. Recrystallization from acetonitrile gave the product (18 g), mp 57°-61° C.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].S(=O)(=O)(O)O.[CH2:10]1[CH2:20][C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1>O.C(Cl)(Cl)Cl>[NH:1]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:20][C:18]1=[O:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCCc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2ccccc2N1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A solution of sodium azide (25 g, 370 mmol) in water (13 mL) and chloroform (160 mL) is cooled to 0° C. and treated dropwise with concentrated sulfuric acid (11 mL). Stirring is continued for 30 min and the layers separated. The organic layer is dried over anhydrous sodium sulfate, filtered, and α-tetralone (20 g, 137 mmol) is added in one protion with stirring. The resulting solution is heated at 40° C. and concentrated sulfuric acid (38 mL) is added dropwise to maintain the internal temperature at 40-45° C. and stirring continued for 1 h, then cooled to 20° C. and poured into a sepratory funnel. The bottom layer is added dropwise with stirring to ise water (900 mL). The resulting solids are collected by filtration, and dried in vacuo at 40° C. to give 19.7 g of an off-white solid (89%), mp 139-140° C.; MS (ESI+) m/z 162 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:20].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC(F)(F)F)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (116 mg, 0.47 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41062 (160 mg, 0.47 mmol) at RT followed by a 2 N aq. solution of LiOH (0.47 mL, 0.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 30 mg of 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((6-methoxy-2-((2,2,2-trifluoroethyl)amino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride SLA 41064 as a yellow solid (31 mg, 11% yield).
Reaction SMILES: COC(C1N(CC=O)C=C(C(=O)NCC2C=CC(F)=CC=2)C(=O)C=1OCC1C=CC=CC=1)=O.Cl.Cl.N[C@@H](C)CCNCCOC.[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([O:77]CC3C=CC=CC=3)=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH2:70][O:71][CH3:72])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1>CO.ClCCl>[F:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][NH:54][C:55]([C:57]2[C:58](=[O:85])[C:59]([OH:77])=[C:60]3[C:74](=[O:75])[N:64]4[C@@H:65]([CH3:73])[CH2:66][CH2:67][N:68]([CH2:69][CH2:70][O:71][CH3:72])[C@@H:63]4[CH2:62][N:61]3[CH:76]=2)=[O:56])=[CH:49][CH:48]=1
Reactant: COCCN1CC[C@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Agent: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: COCCNCC[C@H](C)N
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COCCN1CC[C@H](C)N2C(=O)c3c(O)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@@H]12
Yield: 60 %

Procedure:
In a manner similar to that described in example Z-35, from 16 (15 mg, 0.034 mmol) and [(3S)-3-Aminobutyl][2-(methyloxy)ethyl]amine bis hydrochloride (19 mg, 0.087 mmol), (4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid after silica gel chromatography (1-12% methanol/dichloromethane). This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a yellow solid (9 mg, 60%, 2 steps). 1H NMR (CDCl3) δ 12.56 (s, 1H), 10.51 (m, 1H), 8.29 (s, 1H), 7.32 (m, 2H), 6.98 (m, 2H), 5.03 (m, 1H), 4.65-4.59 (m, 2H), 4.53 (m, 1H), 4.21 (m, 1H), 3.61-3.40 (m, 2H), 3.34-3.13 (m, 3H), 3.08 (m, 1H), 2.94-2.84 (m, 2H), 2.68 (m, 1H), 2.07 (m, 1H), 1.50 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.14 (m, 1H); ES+ MS: 459 (M+1).
Reaction SMILES: [C:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=S)#[N:2].[NH2:13][C@@H:14]1[C:19]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=2[O:17][C:16]([CH3:27])([CH3:26])[C@H:15]1[OH:28].Cl.CN(C)CCCCCN=C=N>CN(C)C=O>[C:1]([N:3]=[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:13][C@@H:14]1[C:19]2[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=2[O:17][C:16]([CH3:26])([CH3:27])[C@H:15]1[OH:28])#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: N#CNC(=S)Nc1ccccc1
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.6 %

Procedure:
To a solution of N-cyano-N'-phenylthiourea (2.11 g, 11.9 mmol) and (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.0 g, 9.1 mmol), title B compound, in dimethylformamide (20 mL) under argon was added 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide hydrochloride (2.23 g, 11.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then partitioned between 1N hydrochloric acid and ethyl acetate. The organic phase was separated and the aqueous phase was reextracted with ethyl acetate. The combined organic extracts were washed with water, sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate/hexanes (7:3) to give a colorless solid which was triturated with ether to yield the title compound (0.35 g), m.p. 215°-216° C.: [α]D25 -33.5° (c=1, MeOH); 1H NMR (DMSO-d 6) δ 9.28 (s, 1 H), 7.58 (d, J=8.0 Hz, 3 H), 7.35 (m, 4 H), 7.15 (m, 1 H), 6.90 (d, J=8.2 Hz, 1 H), 5.92 (br s, 1 H), 4.92 (t, J=9.0 Hz, 1 H), 3.72 (br d, J=5.9 Hz, 1 H), 1.4I, 1.18 (s, 3 H each); 13C NMR (DMSO-d6) 159.2, 156.3, 137.5, 132.6, 132.5, 129.0 124.8, 124.7, 123.6, 119.0, 117.8, 117.0, 102.6, 80.4, 70.9, 51.9, 26.6, 18.6; IR (KBr) 2226, 2179, 1609, 1582, 1491, 1267 cm-1.
Reaction SMILES: [C:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](O)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][C:8]=2[CH3:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[CH3:34][O:35][C:36](=[O:41])[C@H:37]([CH2:39][OH:40])[NH2:38].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:41])[C@@H:37]([NH:38][C:27]([C:24]1[N:16]2[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]3[CH:30]=[CH:31][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[C:8]([CH3:32])[CH:9]=3)[C:19]3[CH:18]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:17]2)=[CH:26][CH:25]=1)=[O:28])[CH2:39][OH:40]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 5, Step E (0.300 g, 0.703 mmol), L-serine methyl ester hydrochloride (0.131 g, 0.844 mmol), 1-hydroxy benzotriazole (0.104 g, 0.773 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.148 g, 0.773 mmol) were combined in amine-free N,N-dimethylformamide (2.8 mL), followed by addition of N,N-diisopropylethylamine (0.307 mL, 1.76 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with water, 1 N hydrochloric acid, 1 N sodium hydroxide and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined, organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 10% methanol in chloroform, to afford 0.330 g of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([CH2:9]CN)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][NH:15]CC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[O:31]=[C:32]1[NH:41][C:40]2[N:39]=[CH:38][C:37](/[CH:42]=[CH:43]/[C:44]([OH:46])=O)=[CH:36][C:35]=2[CH2:34][CH2:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:15]([CH3:14])[C:44](=[O:46])/[CH:43]=[CH:42]/[C:37]2[CH:38]=[N:39][C:40]3[NH:41][C:32](=[O:31])[CH2:33][CH2:34][C:35]=3[CH:36]=2)=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CS(=O)(=O)c1ccc(CCN)cc1
Reactant: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1ccc(S(C)(=O)=O)cc1)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 71 %

Procedure:
According to the procedure of Example 1 (a), except substituting (4-methanesulfonyl-benzyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.400 g, 71%) was prepared as an off-white solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.6-10.65 (m, 1H), 8.38-8.34 (m, 1H), 8.10-8.04 (m, 1H), 7.95-7.89 (m, 2H), 7.57-7.46 (m, 3H), 7.28-7.23 (m, 1H), 4.96-4.72 (m, 2H), 3.20-3.16 (m, 5H), 2.94-2.84 (m, 3H) 2.56-2.49 (m, 2H); MS (APCI) m/e 400 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>Cl.O1CCOCC1.O>[CH3:27][S:28]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]([O:2][CH3:1])=[O:26])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(=O)Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(=O)Nc1ccc(N2CCN(S(C)(=O)=O)CC2)nc1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 4-(5-{[methoxy(oxo)acetyl]amino}pyridin-2-yl)piperazine-1-carboxylate (Intermediate 16, 4 g, 11 mmol) in 4N HCl/dioxan (25 mL) was stood for 16 h then concentrated by evaporation. The residue was dissolved in a mixture of DMF (20 mL) and pyridine (7 mL) then methanesulphonyl chloride (1.28 mL, 16.48 mmol) was added. The mixture was stirred for 3 hours then was diluted with water (50 mL) and extracted with dichloromethane (2×100 mL). The organic extracts were dried and concentrated by evaporation to give the title compound as a solid that was used without further purification; MS m/e MH+ 343.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH:12]([C:15]1[CH:16]=[C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[C:20]=1[NH2:21])([CH3:14])[CH3:13].N1C=CC=CC=1.O>ClCCl>[CH:22]([C:19]1[CH:18]=[C:17]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:16]=[C:15]([CH:12]([CH3:14])[CH3:13])[C:20]=1[NH:21][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:23])[CH3:24]
Reactant: CC(C)c1cc(-c2ccccc2)cc(C(C)C)c1N
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C(=O)Nc2c(C(C)C)cc(-c3ccccc3)cc2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
A solution of 3-methoxybenzoyl chloride (7.54 mL, 55.3 mmol) in DCM (dichloromethane) (50 mL) was added slowly to a 0° C., stirred solution of 3,5-diisopropyl-[1,1′-biphenyl]-4-amine (10 g, 39.5 mmol) and pyridine (5.43 mL, 67.1 mmol) in DCM (100 mL). The mixture was then warmed up and stirred overnight at room temperature. After the reaction was complete, water was added into the reaction mixture. The aqueous mixture was extracted with DCM, and the DCM layer was separated, washed with water (2×), aq. Na2CO3, water (2×) and brine, and dried over anhydrous Na2SO4. Filtration and evaporation gave an off-white solid which was recrystallized from hexane/DCM (2/8) (v/v) to afford a snow white solid (9.93 g, 65%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24].N.C(Cl)Cl>CC#N.CO>[NH2:24][CH2:23][CH2:22][NH:25][C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Cl)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: NCCN
Agent: N
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(NCCN)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C

Procedure:
Dissolve 7-chloro-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a] pyrimidine in 25 mL CH3CN, then add excess ethylenediamine (5 mL) and heat to 80° C. for 3-6 h under N2 with attached reflux condenser. (TLC; product diamine Rf=0.5, aryl chloride Rf=1.0; [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent). Cool to ambient temperature and evaporate to yellow oil. Partition between CH2Cl2 (50 mL) and 1.0 N NaOH (50 mL), and extract aqueous layer 2×30 mL CH2Cl2. Pool organic layers, dry over Na2SO4, filter and evaporate to yellow-white foam (1.25 g). Use without further purification. LCMS=344.4 (MH+); 342.3 (M−).
Reaction SMILES: N1(N[C:7]2[NH:8][C:9]3[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([O:17]C)[C:10]=3[N:11]=2)CCN=C1.C(C1C2NC=NC=2C(C)=CC=1[NH:31][N:32]1[CH2:36][CH2:35][N:34]=[CH:33]1)C.COC.Cl.[NH+]1C=CC=CC=1>>[OH:17][C:12]1[C:10]2[N:11]=[CH:7][NH:8][C:9]=2[C:15]([CH3:16])=[C:14]([NH:31][N:32]2[CH2:36][CH2:35][N:34]=[CH:33]2)[CH:13]=1
Reactant: COc1ccc(C)c2[nH]c(NN3C=NCC3)nc12
Reactant: CCc1c(NN2C=NCC2)cc(C)c2nc[nH]c12
Agent: COC
Agent: Cl
Agent: c1cc[nH+]cc1
Product: Cc1c(NN2C=NCC2)cc(O)c2nc[nH]c12

Procedure:
(2-imidazolinylamino)-7-methoxy-4-methylbenzimidazole is made in the same manner as 4-ethyl-5-(2-imidazolinylamino)-7-methylbenzimidazole except that 2-methoxy-5-methylacetanilide is used instead of 3-ethyl-6-methylacetanilide (see Example 2). Cleavage of the methyl ether is achieved with pyridinium hydrochloride to afford 7-hydroxy-5-(2-imidazolinylamino)-4-methylbenzimidazole.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:11])=[C:8]([OH:10])[CH:9]=1.Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[Cl:11][C:7]1[CH:6]=[CH:5][C:4]([NH2:3])=[CH:9][C:8]=1[O:10][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(Cl)c(OCCN2CCCC2)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a stirring RT slurry of NaH (0.10 g of a 60% by weight oil dispersion, 2.5 mmol) in DMF (2 mL) was added 5-amino-2-chlorophenol (0.20 g, 1.4 mmol). The mixture was stirred for 10 min before adding 1-(2-chloroethyl-pyrrolidine hydrochloride (0.17 g, 1.0 mmol). The reaction was heated at 80° C. for 15 h. The reaction was quenched with water, treated with 1N NaOH, and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield title compound. MS: (MH+)=241.2; Calc'd 240.74 for C12H17ClN2O.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[Cl:23].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[Cl:23]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N)c(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCNCC2)cc1Cl
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of tert-butyl 4-(4-amino-3-chlorobenzoyl)piperazine-1-carboxylate (45.3 mmol, 15.4 g), dichloromethane (50 mL) and 2,2,2-trifluoroacetic acid (136 mmol, 15.50 g) were stirred for 24 hours. The reaction was concentrated under reduced pressure and was then basified with potassium carbonate (aqueous). The aqueous was extracted with ethyl acetate and then dichloromethane to give the title compound (7.7 g).
Reaction SMILES: C1(O[C:8](=[O:44])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:26]4[C:25](=[O:27])[N:24]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:23][C:22]([CH3:35])([CH3:34])[O:21][C:20]=4[N:19]=[C:18]([N:36]4[CH2:42][CH:41]5[O:43][CH:38]([CH2:39][CH2:40]5)[CH2:37]4)[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH3:45][C:46]1[O:50][N:49]=[C:48]([NH2:51])[CH:47]=1.CN(C=O)C>C1COCC1>[CH3:35][C:22]1([CH3:34])[O:21][C:20]2[N:19]=[C:18]([N:36]3[CH2:37][CH:38]4[O:43][CH:41]([CH2:40][CH2:39]4)[CH2:42]3)[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:51][C:48]4[CH:47]=[C:46]([CH3:45])[O:50][N:49]=4)=[O:44])=[CH:11][CH:12]=3)[C:26]=2[C:25](=[O:27])[N:24]([CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[CH2:23]1
Reactant: CC1(C)CN(C2CCOCC2)C(=O)c2c(nc(N3CC4CCC(C3)O4)nc2-c2ccc(NC(=O)Oc3ccccc3)cc2)O1
Reactant: Cc1cc(N)no1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Nc2ccc(-c3nc(N4CC5CCC(C4)O5)nc4c3C(=O)N(C3CCOCC3)CC(C)(C)O4)cc2)no1
Temperature: 100 °C
Yield: 11.9 %

Procedure:
50 mg (83.38 μmol) of {4-[8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-6-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}carbamic acid phenyl ester are placed in a microwave reactor and 25 mg (0.25 mmol) of 5-methylisoxazol-3-ylamine are added. 2 ml of DMF and 1 ml of THF are added. The reaction mixture is heated in a Biotage microwave machine for 30 minutes at 100° C. 100 mg (1.0 mmol) of 5-methylisoxazol-3-ylamine are added and the mixture is heated for 2 hours at 110° C. A further 300 mg (3 mmol) of 5-methylisoxazol-3-ylamine are added and the mixture is heated for 2 hours at 110° C. The solvents are evaporated off. The residue is taken up in water and the insoluble material is filtered off, washed three times with water, taken up in MeOH/DCM and dried. The residue is chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0/100 v/v) up to (5/95 v/v) to give 6 mg of 1-{4-[8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-6-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}-3-(5-methylisoxazol-3-yl)urea.