Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[C:11]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=[O:14].S1(CCCC1)(=O)=O>O>[OH:9][C:3]1[C:2]2[NH:1][C:13](=[O:14])[C:12]3[CH:16]=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[N:19][C:11]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
Reactant: Nc1cccc(O)c1N
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1Nc2c(O)cccc2Nc2nc(C(F)(F)F)ccc21
Temperature: 150 °C

Procedure:
A mixture of 2,3-diaminophenol (79 g, 0.64 mol), 2-chloro-6-(trifluoromethyl)nicotinic acid (100 g, 0.44 mol) and sulfolane (1 L) was heated under nitrogen at 150° C. overnight. After cooling to rt, the reaction mixture was poured into water. The precipitate was collected by filtration, and was re-dissolved in EtOAc, washed with water and brine, dried over MgSO4, filtered and concentrated to give 7-hydroxy-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][C@@H:10]1[CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:8]([CH3:26])[C@@H:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][C@@H:10]1[CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC[C@H]1Cn2c(cc3cc(Br)ccc32)[C@H]1NCc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(Cc1ccccc1)[C@@H]1c2cc3cc(Br)ccc3n2C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
The product of Step 1 (710 mg, 2 mmol) was suspended in 1,2-dichloroethane with formaldehyde (0.4 mL of 37% aqueous solution, 5 mmol). Sodium triacetoxyborohydride (848 mg, 4 mmol) was added to the mixture. The mixture stirred vigorously at room temperature for 30 min. The mixture was washed with aqueous saturated NaHCO3 and run through a plug of silica gel, eluting with EtOAc, to give the product (690 mg, 90%).
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[N:19][C:20]=1[CH:21](OC)[O:22]C)[N:17]([C:26]([NH:28][C:29]1[CH:34]=[C:33]([NH:35][CH2:36][C:37]([OH:43])([CH3:42])[CH2:38][N:39]([CH3:41])[CH3:40])[C:32]([C:44]#[N:45])=[CH:31][N:30]=1)=[O:27])[CH2:16][CH2:15][CH2:14]2)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1.O>[C:44]([C:32]1[C:33]([NH:35][CH2:36][C:37]([OH:43])([CH3:42])[CH2:38][N:39]([CH3:40])[CH3:41])=[CH:34][C:29]([NH:28][C:26]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([CH2:10][OH:9])=[C:20]([CH:21]=[O:22])[N:19]=3)[CH2:14][CH2:15][CH2:16]2)=[O:27])=[N:30][CH:31]=1)#[N:45]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(NCC(C)(O)CN(C)C)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC(C)(O)CNc1cc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)ncc1C#N

Procedure:
Concentrated hydrochloric acid (0.17 ml) was added to a solution of 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-((3-(dimethylamino)-2-hydroxy-2-methylpropyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 78D, 33 mg, 0.053 mmol) in THF (1 ml) and water (0.5 ml) at room temperature. After stirring for 18 h at room temperature saturated aqueous NaHCO3 was then added, the mixture extracted with DCM (2×), the organic layers dried over Na2SO4 and evaporated. The residue was triturated with Et2O to give the title compound.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13](O)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][C:29]1([CH3:37])[O:34][C:33](=[O:35])[CH2:32][C:31](=[O:36])[O:30]1.N1C=CC=CC=1>C(Cl)Cl>[C:1]12([O:11][CH2:12][C:13](=[C:32]3[C:33](=[O:35])[O:34][C:29]([CH3:37])([CH3:28])[O:30][C:31]3=[O:36])[OH:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)COC12CC3CC(CC(C3)C1)C2
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=C(O)COC23CC4CC(CC(C4)C2)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of (adamantan-1-yloxy)-acetic acid (Example 216, step a) (32.3 g, 0.153 mol) and 1,1′-carbonyl-diimidazole (27.6 g, 0.17 mol) in anhydrous DCM (600 ml) was stirred at 0° C. for 15 min, then at room temperature for 75 min. The mixture was concentrated in vacuo (˜300 ml) and the solution was added dropwise over 20 min to a solution of 2,2-dimethyl-1,3-dioxan-4,6-dione (22.1 g, 0.153 mol) and pyridine (30 ml, 0.371 mol) in anhydrous DCM (450 ml) at 0° C. under argon. The mixture was allowed to warm to room temperature and stirred for 16 h. The solution was washed with 2M HCl (2×500 ml), brine (500 ml) and dried (MgSO4). Filtration and evaporation gave the product as a white solid, which was washed with hexane, isolated by filtration and dried (50.1 g, 97%). 1H NMR (300MHz, CDCl3) 4.92 (2H, s), 2.19 (3H, br s), 1.82 (6H, s), 1.74 (6H, s), 1.64 (6H, m).
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([NH:9][CH2:10][CH2:11][S:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:8])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>O>[F:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH2:10][CH2:11][SH:12])=[O:8])=[CH:32][CH:33]=1
Reactant: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(CF)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NCCS)c1ccc(CF)cc1
Reaction time: 0.08 h

Procedure:
To 1.4 mg (3.0 μmol) of 4-fluoromethyl-N-[2-(tritylsulphanyl)ethyl]benzamide was added 50 μl of TFA/TIS/H2O(95:2.5:2.5) mixture. The flask was swirled gently for 5 minutes and then concentrated in vacuo. LC-MS analysis (column Phenomenex Luna 3 μm C18(2) 50×2.00 mm; solvents: A=water/0.1% HCOOH and B=acetonitrile/0.1% HCOOH; gradient 5-60% B over 10 min; flow 0.3 ml/min, UV detection at 214 and 254 nm, ESI-MS) gave a peak (tR 6.8 min) with m/z at 214 corresponding to MH+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C@@H:13]([NH:21]C(OC(C)(C)C)=O)[CH2:14][CH2:15][C:16]2[N:17]=[N:18][NH:19][N:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:29])[C@@H:13]([NH2:21])[CH2:14][CH2:15][C:16]2[N:17]=[N:18][NH:19][N:20]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 120 mg 4-[(S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid ethyl ester in 1.5 ml dichloromethane were added 0.4 ml TFA. After 2 h stirring at RT the solvents were removed and the residue was used without further purification. Yield: 130 mg.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13]Br)[CH:8]=1)#[N:6].C(N(CC)CC)C>CC(C)=O>[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][N:3]([CH3:4])[CH3:2])[CH:8]=1)#[N:6]
Reactant: N#Cc1ccnc(CBr)c1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)Cc1cc(C#N)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
Dimethylamine hydrochloride (4.78 g, 58.6 mmol) was added to a solution of 4-cyano-2-bromomethylpyridine (3.95 g, 19.5 mmol) and triethylamine (13.58 mL, 97.7 mmol) in acetone (40 mL). The reaction mixture was stirred overnight at room temperature in a sealed tube. The reaction mixture was concentrated under reduced pressure and partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was separated and washed with water, saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 99:1 methylene chloride/methanol) gave the desired 4-cyano-2-(dimethylamino)methylpyridine (2.10 g): 1H NMR (300 MHz, CDCl3) δ 8.73 (d, J=5.0 Hz, 1H), 7.71 (s, 1H), 7.41 (dd, J=5.0, 1.2 Hz, 1H), 3.65 (s, 2H), 2.31 (s, 6H); ESI MS m/z 162 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[CH:16]1([CH2:19][NH:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH2:17]1>ClCCl.CO>[CH:16]1([CH2:19][N:20]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=2[O:14][CH3:15])[CH2:21][CH2:22][CH3:23])[CH2:18][CH2:17]1
Reactant: CCCNCC1CC1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Solvent: ClCCl
Solvent: CO
Product: CCCN(CCOc1ccc([N+](=O)[O-])cc1OC)CC1CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.62 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.51 mL (10.57 mmol) of cyclopropylmethylpropylamine. Yield: 0.95 g (85% of theory); C16H24N2O4 (M=308.37); calc.: molecular ion peak (M+H)+: 309; found: molecular ion peak (M+H)+: 309; Rf value: 0.4 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=2[O:30][CH3:31])[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:7]=1.Cl[C:37]1C=CC(OC)=C(S(Cl)(=O)=O)[CH:42]=1>>[CH2:37]([O:23][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:12]([NH:11][S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:34][CH3:35])(=[O:9])=[O:10])[CH:13]=2)=[CH:26][CH:25]=1)[CH3:42]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Nc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(OC)c1OC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(NS(=O)(=O)c3cc(Cl)ccc3OC)c(OC)c(OC)c2)cc1

Procedure:
4-[3-(5-Chloro-2-methoxy-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid, MS (ISP): m/e=519.2 (M−H), was prepared in analogy to example 31, steps A to D. Step C was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 4-[3-(5-chloro-2-methoxy-benzenesulfonylamino)-4,5-dimethoxy-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D
Reaction SMILES: O.[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:7]([CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=2)[NH:6][N:5]=1)[CH3:3].[OH:31]OS([O-])=O.[K+]>ClCCl>[CH2:2]([C:4]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:7]([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:30])=[O:31])=[CH:27][CH:28]=2)[NH:6][N:5]=1)[CH3:3]
Reactant: CCc1n[nH]c(CCOc2ccc(SC)cc2)c1Oc1cc(C#N)cc(C#N)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CCc1n[nH]c(CCOc2ccc(S(C)=O)cc2)c1Oc1cc(C#N)cc(C#N)c1
Yield: 37.2 %

Procedure:
Wet alumina was prepared by adding water (1 ml) to Brockman grade I alumina (5 g). A sample of this material (160 mg) was added to a stirred solution of the sulfide from Example 1 (106 mg, 0.16 mmol) in dichloromethane (1 ml), followed by oxone (98 mg, 0.16 mmol). The reaction mixture was heated at reflux for 45 minutes, before being filtered. The solids were washed with dichloromethane (10 ml) and the combined organics were concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (100:0, 98:2 and 96:4, by volume) to give the title compound as a colourless oil (25 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:22]2[N:23]([CH3:28])[N:24]=[CH:25][C:26]=2[Br:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:17][C:16]=2[C:22]2[N:23]([CH3:28])[N:24]=[CH:25][C:26]=2[Br:27])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(Br)c1-c1cc(NC(=O)c2ccc(F)cc2)ccc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
A mixture of 3-[4-amino-2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.2 mmol), 4-fluorobenzoic acid (34 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 15 min. The crude was purified by HPLC to give 3-[2-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-benzoylamino)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (36 mg, 32%) as a white solid. MS found, 573.5 and 575.5.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=3[N:10]=[C:9]2[CH:19]([F:21])[F:20])[N:5]=[C:4]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[N:3]=1.Cl.[CH:36]12[O:43][CH:40]([CH2:41][CH2:42]1)[CH2:39][NH:38][CH2:37]2.CCN(C(C)C)C(C)C>C1COCC1>[F:20][CH:19]([F:21])[C:9]1[N:8]([C:6]2[N:7]=[C:2]([N:38]3[CH2:37][CH:36]4[O:43][CH:40]([CH2:41][CH2:42]4)[CH2:39]3)[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]3)[N:5]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[N:10]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture of tert-butyl 4-{4-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate (550 mg, 1.11 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (215 mg, 1.44 mmol) and DIPEA (0.77 mL, 4.44 mmol) in THF (20 mL) was stirred at room temperature overnight. The solvent was removed under vacuum and the residue diluted with water. The resulting precipitate was washed with water, dissolved in CH2Cl2, dried (Na2SO4) and recrystallized from CH2Cl2/MeOH to give 540 mg (85% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: mp (CH2Cl2/MeOH) 181-183° C.; 1H NMR (CDCl3) δ7.89 (dd, J=8.4, 0.6 Hz, 1H), 7.49 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.6, 1H), 4.48 (d, J=8.0 Hz, 2H), 4.33 (dd, J=12.6, 8.9 Hz, 2H), 4.05 (s, 3H), 3.87 (br s, 4H), 3.53 (br s, 4H), 3.29 (ddd, J=32.8, 13.1, 1.6 Hz, 2H), 1.99 (dd, J=8.3, 4.4 Hz, 2H), 1.79 (m, 2H), 1.50 (s, 9H); Anal. Calcd. for C27H34F2N8O4.0.05H2O: C, 56.55; H, 6.0; N, 19.5. Found: C, 56.2; H, 6.0; N, 19.6.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13][C:12]2=O)=[O:8]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][CH:13]=[C:12]2[Cl:3])=[O:8]
Reactant: COC(=O)c1ccc2[nH]ncc(=O)c2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nncc(Cl)c2c1
Reaction time: 1.15 h
Yield: 1.3 %

Procedure:
Thionyl chloride (5 mL, 68.5 mmol) and N,N-dimethylformamide (3 drops) were added to 4-oxo-1,4-dihydro-cinnoline-6-carboxylic acid methyl ester (212 mg, 1.04 mol), and the solution was stirred for 1.15 hours under reflux. Toluene was added to the reaction mixture, which was then evaporated in vacuo. Ethyl acetate was added to the residue the organic layer was washed with an ice water, dried over anhydrous magnesium sulfate, then, evaporated in vacuo, and the title compound (192 mg, 0.862 mmol, 82.9%) was obtained. This was used in the next reaction without purification.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].C(N(C(C)C)C(C)C)C.[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][CH2:49][NH2:50]>CN(C)C=O>[F:35][C:2]1([F:1])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:50][CH2:49][CH2:48][CH2:47][N:46]([CH3:51])[CH3:45])=[O:27])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.019 g (0.19 mmole) of N,N-dimethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-70:30) gave 0.045 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-279) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[C:11]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][N:20]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH2:26])=[O:27])=[CH:21][N:20]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(Oc3ccc(C(N)=O)cn3)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2cccc3c2CNCC3)nc1
Reaction time: 12 h
Yield: 57.4 %

Procedure:
Combine 8-(5-Carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (249.6 mg, 1.01 mmol), CH2Cl2 (25 ml), and TFA (10 ml) at room temperature under nitrogen atmosphere. After the reaction stirs for 12 hours then concentrate under reduced pressure. Solubilize the mixture in MeOH and add to a 2 g SCX Column (pre-treated with 5% AcOH-MeOH), wash several times with MeOH, and elute the product with 1N NH3 MeOH to afford 156.1 mg, 0.58 mmol (57% yield) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[NH3:14]>S([O-])([O-])(=O)=O.[Cu+2]>[NH2:14][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: N
Reactant: O=C(O)c1cc(C(=O)O)c(Br)cn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: Nc1cnc(C(=O)O)cc1C(=O)O
Temperature: 160 °C
Reaction time: 20 h

Procedure:
A mixture of 500 mg of 5-bromo-pyridine-2,4-dicarboxylic acid from Example 2, 100 mg of copper sulfate and 20 ml of ammonia solution (d=0.91) is heated at 160° C. in an autoclave for 4 hours. The solution is evaporated to dryness, the solid is heated with a little methanol and the insoluble material is removed from the solution. After 20 hours, a white solid precipitates out at 0° C. and is filtered off and dried.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:7]=[CH:6][NH:5][C:4]=1[C:8]([OH:10])=O.[CH3:13][CH:14]([CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[N:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]>>[CH3:13][CH:14]([CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[N:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:8]([C:4]3[NH:5][CH:6]=[N:7][C:3]=3[C:2]([F:1])([F:12])[F:11])=[O:10])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]
Reactant: O=C(O)c1[nH]cnc1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3[nH]cnc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 5-trifluoromethyl-3H-imidazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (48% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.03, 7.86, 7.70, 6.99, 3.80, 3.46, 1.75-1.62, 1.48, 0.92. MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][CH:8]=[CH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][CH:8]=[CH2:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CCC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
4-[1-(1-Cyclopentylbut-3-en-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (13 mg, 0.030 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The resulting solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was dissolved in THF (2 mL), and 6 N NaOH (1 mL) was added. The mixture was stirred at room temperature for 1 hour, and then was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (10 mg, 80%).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]=[C:6]([CH3:27])[CH:7]=[CH:8][CH2:9][C:10]1([C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=2)[CH2:12][CH2:11]1)C>CO>[C:23]([C:15]1[CH:14]=[C:13]([C:10]2([CH2:9]/[CH:8]=[CH:7]/[C:6](/[CH3:27])=[CH:5]/[C:4]([OH:28])=[O:3])[CH2:11][CH2:12]2)[CH:18]=[C:17]([C:19]([CH3:21])([CH3:22])[CH3:20])[CH:16]=1)([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOC(=O)C=C(C)C=CCC1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Solvent: CO
Product: CC(/C=C/CC1(c2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1)=C\C(=O)O

Procedure:
The above ethyl ester 11 (712 mg, 2.18 mmol) in 35 mL MeOH was hydrolyzed as described for Example 1 to give the crude acid. The crude mixture was purified by HPLC (80% MeOH/20% 10 mmol NH4OAc+0.3% AcOH) to give 390 mg (60%) of pure (2E, 4E)-6-[1-(3,4-diethylbenzene)-cyclopropyl]-3-methyl-2,4-hexadienoic acid (12). 1H NMR (400 MHz, CDCl3) δ7.04 (m, 3H, aromatic), 6.15 (dt, J=15.6 and 6.8 Hz, 1H, vinylic CH), 6.05 (d, J=15.6 Hz, 1H, vinylic CH), 5.69 (s, 1H, vinylic CH), 2.62 (q, J=7.5 Hz, 4H, aliphatic 2CH2), 2.43 (d, J=6.8 Hz, 2H, allylic CH2), 2.23 (s, 3H, aliphatic CH3), 1.20 (m, 6H, aliphatic 2CH3), 0.84 (dd, J=6.2, 4.7 Hz, 2H, aliphatic CH2), 0.73 (dd, J=5.4, 4.1 Hz, 2H, aliphatic CH2).