Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:24]1([NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:31][C:19](=[O:20])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccccc1NC(=O)c1ccc(CNc2ccc(N3CCOCC3)cc2)cc1

Procedure:
To a solution of acid 402a (2.61 g; 8.36 mmol; 1 eq), 1,2-phenylenediamine (903 mg; 8.36 mmol; 1 eq) and BOP (3.70 g; 8.36 mmol; 1 eq) in dry DMF (20 ml) was added Et3N (4.64 ml; 33.4 mmol; 4 eq). After stirring overnight most of the DMF was removed under reduced pressure and chromatographed (Hex:EtAcO: 1:2/EtAcO). The crystal 402 was obtained in 70% (2.35 g). 1H-NMR (300.07 MHz, DMSO-d6) δ (ppm): 9.65 (s, 1H), 7.97 (d, J=7.9, 2H), 7.53 (d, J=7.9, 2H), 7.22 (d, J=7.5, 1H), 7.03 (dd, J=7.0, 7.5, 1H), 6.83 (d, J=7.9, 1H), 6.77 (d, J=8.8, 2H), 6.65 (dd, J=7.5, 7.0,1 H), 6.57 (d, J=8.8, 2H), 4.93 (bs, 2H), 4.36 (d, J=5.7, 2H), 3.75 (m, 4H), 2.93 (m, 4H). LRMS: calc 402.49. found: 403.4.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([OH:13])=O)[CH:6]=1)=[O:4].[Cl-].[Mg+2].[Cl-].Cl.[CH2:18]([NH2:20])[CH3:19].C(N(CC)CC)C>ClCCl>[CH2:18]([NH:20][C:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][N:8]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH3:19]
Reactant: COC(=O)c1ccnc(C(=O)O)c1
Reactant: CCN
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cc(C(=O)OC)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
A mixture of 4-(methoxycarbonyl)picolinic acid (1.00 g, 5.12 mmol) and magnesium chloride (312 mg, 3.28 mmol) in dichloromethane (10 mL) is stirred at room temperature for 0.5 hour. Then, ethylamine hydrochloride (627 mg, 7.69 mmol) and triethylamine (1.07 mL, 7.69 mmol) are added. After stirring at room temperature for 20 hours, the mixture is poured onto water (50 mL). The aqueous phase is extracted with EtOAc (50 mL×2). The combined organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (3:11:1) to give 525 mg (49% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C.O.NN>C(O)C>[NH2:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([CH3:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: Cc1cc([N+](=O)[O-])cc2c1NC(=O)CC2
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(N)cc2c1NC(=O)CC2
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a suspension of 8-methyl-6-nitro-3,4-dihydro-2(1H)-quinolinone (25 g), activated charcoal (8 g) and ferric chloride (2.5 g) in ethanol (700 ml) was dropwise added hydrazine monohydrate (30 g) over the period of 20 minutes at 77° C., and the mixture was stirred for 1 hour. Then, to the reaction mixture were added activated charcoal (3 g) and ferric chloride (1.5 g) and was dropwise added hydrazine monohydrate (10 g). After refluxed for 1.5 hours, the reaction mixture was filtered and the insoluble material was washed with ethanol and a mixture of ethanol and chloroform successively. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 6-amino-8-methyl-3,4-dihydro-2(1H)-quinolinone (19.5 g).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12](C(C)(C)C)[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].S(Cl)([Cl:28])(=O)=O.S(=O)=O>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([Cl:28])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Reactant: O=S(=O)(Cl)Cl
Agent: O=S=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1cc(Cl)c(O)c(C(C)(C)C)c1)OCC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
71.2 g of 3,5-di-tert. butyl-4-hydroxybenzyl-phosphonic acid diethyl ester are dissolved in 200 ml of carbon tetrachloride. After addition of a few drops of pyridine, 40.5 g of sulphuryl chloride are added dropwise, with stirring, at about 0° C in the course of 45 minutes. The reaction mixture is then further stirred for 10 hours at room temperature, in the course of which the formation of sulphur dioxide is observed. After the reaction is terminated, the solvent is removed as far as possible completely in vacuo. The semi-crystalline residue is digested with water and washed neutral and finally recrystallised from aqueous isopropanol in order to purify it. Instead of isopropanol it is also possible to use ethylene glycol monomethyl ether. Toluene is also suitable for effecting recrystallisation, but the crude product must in this case be freed from water beforehand. The 3-chloro-5-tert. butyl-4-hydroxybenzyl-phosphonic acid diethyl ester is obtained in the form of colourless crystals (stabiliser 1) with a melting point of 116° C.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([NH2:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](O)(=O)C.C(N)=N>C(O)C>[CH2:7]([C@@H:8]1[CH2:9][NH:10][CH:12]=[N:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: NC[C@H](N)Cc1ccccc1
Agent: N=CN
Solvent: CCO
Product: C1=N[C@H](Cc2ccccc2)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a solution of (2R)-3-phenyl-1,2-propanediamine (0.20 g, 1.33 mmol) in ethanol (5 ml) was added formamidine acetate (0.15 g, 1.45 mmol) and the mixture was stirred overnight at room temperature. The solvent was evaporated, sodium hydroxide (2N, 5 ml) was added and the mixture was extracted 3 times with dichloromethane (10 ml). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent:ethyl acetate/methanol=90:10) to yield a colorless oil (0.20 g, 92%); MS (ISP): 161.4 ((M+H)+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:3]1.C([O-])(=O)C.[Na+].[Br:27]Br.C(Cl)Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([Br:27])=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:21])=[N:3]1
Reactant: BrBr
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1scc(Cl)c1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(Br)c(Cl)c1Cl
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a mixture of 1-methyl-3-(2-chloro-6-fluorophenyl)-5-(3,4-dichlorothien-2-yl) [1,2,4]triazole (33.4 g, 92.1 mmol) and sodium acetate (7.6 g, 92.1 mmol) in acetic acid (250 mL) was added bromine (58.9 g, 368.4 mmol) dropwise at a rate which maintained the reaction temperature below 35° C. The resulting mixture was slowly heated to 70° C. and stirred for 2.5 hours, cooled to 50° C. and stirred overnight, and cooled to room temperature. TLC analysis (methylene chloride) indicates full consumption of the starting material. The reaction was slowly poured into a mixture of 10% aqueous sodium bisulfite and ice (300 mL), and the resulting pale yellow suspension was stirred for 20 minutes. The solids were collected by vacuum filtration, washed with water, and dissolved in methylene chloride. The organics were dried (sodium sulfate), filtered, and the solvent evaporated at reduced pressure to give 39.3 g (96%) of desired product as a tan solid: mp 178-180° C. 1H NMR (CDCl3) δ4.04 (s, 3H), 7.08-7.14 (Ar-m, 1H), 7.29-7.40 (Ar-m, 2H).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=CC=1)([O-])=O.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH:38]=1>O1CCCC1>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:47][CH2:46][CH2:45][CH2:44][CH2:43][C:39]2[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=2)=[O:10])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: NCCCCc1cccnc1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)c(OC)c2)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NCCCCc2cccnc2)c2ccc(OC)c(OC)c2)cc1OC
Yield: 71.8 %

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3,4-dimethoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (4.9 g) and 3-pyridinebutanamine (1.5 g) in tetrahydrofuran (25 mL) was stirred for 17 hours at room temperature and was then worked up in the usual manner. The crude amide was crystallized from ethyl acetate-hexane to provide 3.6 g of (E)-5,5-bis(3,4-dimethoxyphenyl)-N-[4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 145°-146° C. Anal. Calculated for C30H34N2O5 : C, 71.69; H, 6.82; N, 5,57 Found: C, 71.33; H, 6.93; N, 5.72.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][C:15]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27](=O)([O-])[O-:28].[K+].[K+]>CN(C=O)C>[CH2:6]([N:13]1[C:17]([C:18]([F:20])([F:21])[F:19])=[CH:16][C:15]([C:22]2[O:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=2)=[N:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1cc(-c2ccco2)nn1Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2cc(C(F)(F)F)n(Cc3ccccc3)n2)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
10 ml of dry DMF were initially charged at 10° C., 1.9 g (12.4 mmol) of phosphorus oxychloride were added dropwise and the mixture was stirred for 30 min. A solution of 3 g (10.3 mmol) of 1-benzyl-3-(2-furyl)-5-trifluoromethylpyrazole in 10 ml of DMF was added dropwise, and the mixture was stirred at RT overnight. The mixture was poured into ice-water and adjusted to pH 9 using potassium carbonate solution. The precipitated product was filtered off with suction and dried in a vacuum drying cabinet at 50° C. This gave 3.3 g (100%) of the title compound. m.p.: 76.5-77.5° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CO>[Cl:19][CH2:18][CH2:17][CH2:16][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: ClCCCOc1ccc(-n2ccnc2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 20.3 %

Procedure:
To a stirring solution of 4-(imidazol-1-yl)phenol (20 g, 125 mmol) and NaOH (5.0 g, 125 mmol) in methanol (600 mL) was added 1-bromo-3-chloropropane (49 mL, 500 mmol). The reaction was stirred for 18 hours at 70° C. under nitrogen, concentrated, and partitioned between 1.0N NaOH/CH2Cl2. The organic phase was dried and concentrated to afford crude product which was purified by HPLC (5% CH3OH/CH2Cl2) to give 6.0 g (20%) of 1-[4-(3-chloropropoxy)phenyl]-1H-imidazole as a brown solid: mp 53°-55° C., 1H NMR (CDCl3): δ7.80 (brs, 1H), 7.30 (m, 3H), 7.20 (bs, 1H), 4.16 (t, J=6.0 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 2.30 (m, 2H).
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: Nc1cccc(O)c1N
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1Cl
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: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2O[CH:3]12.[NH2:16][C:17]1[NH:18][C:19]2[C:24]([C:25](=[O:27])[N:26]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[CH3:1][C:2]1([CH3:15])[CH:3]=[C:4]([NH:16][C:17]2[NH:18][C:19]3[C:24]([C:25](=[O:27])[N:26]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Nc1nc(=O)c2ccccc2[nH]1
Product: CC1(C)C=C(Nc2nc(=O)c3ccccc3[nH]2)c2cc(C#N)ccc2O1

Procedure:
Following the procedure in Example 1, using 2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 2-amino-1H-quinazolin-4-one as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.C(O)(C(F)(F)F)=O.[NH:16]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=[N:17]1>CC#N>[I:8][C:19]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:16][NH:17][CH:18]=1
Reactant: CCOC(=O)c1ccn[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1n[nH]cc1I
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.4 %

Procedure:
NIS (8.83 g, 39.2 mmol) and TFA (0.825 mL, 10.70 mmol) were added to a stirred solution of ethyl 1H-pyrazole-5-carboxylate (5 g, 35.7 mmol) in CH3CN (120 mL) under Ar. The reaction mixture was stirred for 6 hr at rt, concentrated, diluted with a saturated aqueous solution of NaHCO3, and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 10-50%) to afford the title product (8.31 g, 31.2 mmol, 88% yield) as a white solid. tR: 3.47 min (HPLC 1); tR: 0.72 min (LC-MS 2); ESI-MS: 267 [M+H]+ (LC-MS 2); Rf=0.55 (hexane/EtOAc 1:1).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:14])=[C:5]([C:10]([F:13])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:14][C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([F:13])[CH:11]=[CH:12][C:3]=1[CH2:2][N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: COC(=O)c1c(F)ccc(CBr)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a room temperature solution of methyl 3-(bromomethyl)-2,6-difluorobenzoate (14.24 g, nominally 51.2 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (9.1 g, 50.24 mmol, 1.0 equiv) in DMF (50 mL) was added K2CO3 (27.8 g, 201 mmol, 4.0 equiv) as a solid. The resulting mixture was allowed to stir overnight. The reaction mixture was diluted with EtOAc and washed repeatedly with H2O. The combined aqueous layers were washed once with EtOAc, and the combined organic layers were washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (10%-60% EtOAc/hexanes) provided tert-butyl 4-(2,4-difluoro-3-(methoxycarbonyl)benzyl)piperazine-1-carboxylate (7.70 g, 41.4% over two steps). LCMS m/z (APCI)=371.2 (M+H).
Reaction SMILES: [CH:1]1([N:6]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:10][CH2:9][C@H:8]([N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.NN>CO>[NH2:19][C@H:8]1[CH2:9][CH:10]=[CH:11][C@@H:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]1=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: N[C@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of 2-[(3S,7S)-1-cyclopentyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-1H-isoindole-1,3(2H)-dione (75 mg) in MeOH (3 ml), was added hydrazine hydrate (21 mg) at RT under N2. The mixture was allowed to stir overnight at RT. The reaction was evaporated and the residue was taken up in DCM and washed with water. The organics were dried (Na2SO4), filtered and evacuated to afford the title compound (40 mg, 79% crude yield) as a crude, yellow oil. This crude oil was not characterized or purified further before taken on to the coupling step.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[Cl:44][C:45]1[CH:46]=[C:47]([C@H:53]([NH2:56])[CH2:54][CH3:55])[CH:48]=[N:49][C:50]=1[O:51][CH3:52].C(N(CC)CC)C>CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([C@H:53]([NH:56][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:54][CH3:55])[CH:48]=[N:49][C:50]=1[O:51][CH3:52]
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1cnc(OC)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1cnc(OC)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then (R)-1-(5-chloro-6-methoxy-pyridin-3-yl)-propylamine hydrochloride (70 mg, 0.3 mmol) and triethylamine (82 mg, 0.81 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 103 mg (83%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(5-chloro-6-methoxy-pyridin-3-yl)-propyl]-amide as white solid. LC/MS (method 2): Rt=1.24 min; m/z=461.12 (M+H+). 1H-NMR: δ (ppm)=8.08 (2H, m), 7.86 (1H, s), 7.19 (1H, s), 4.97 (1H, d), 4.83-4.89 (2H, m), 3.80-4.30 (8H, m), 3.68 (2H, bs), 2.03-2.10 (1H, m), 1.99-1.92 (1H, m), 1.72-1.84 (3H, m), 1.52-1.59 (1H, m), 1.18-1.19 (3H, d), 0.87 (3H, t).
Reaction SMILES: [O:1]1[C:12]2[C:13]3[C:8]4[C:9]([O:14][CH2:15][CH2:16][C:7]=4[N:6]=[N:5][C:4]=3[CH2:3][CH2:2]1)=[CH:10][CH:11]=2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>Cl>[CH:17](=[C:16]1[C:7]2[N:6]=[N:5][C:4]3[C:3](=[CH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:2][O:1][C:12]4=[CH:11][CH:10]=[C:9]([C:8]=2[C:13]=34)[O:14][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: c1cc2c3c(nnc4c3c1OCC4)CCO2
Agent: Cl
Product: C(=C1COc2ccc3c4c(nnc1c24)C(=Cc1ccccc1)CO3)c1ccccc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 0.20 g of 2,3,6,7-tetrahydro-dipyrano-[4,3,2-de:2',3',4'-ij]-phthalazine and 5.0 g of benzaldehyde is heated up to 130° C. Then 6 drops of concentrated hydrochloric acid are added and the mixture is stirred for 30 minutes at 130° C, after which the mixture is evaporated to dryness in vacuo. The residue is crystallised from n-butanol yielding 3,6-di-benzylidene-2,7-dihydrodipyrano-[4,3,2-de:2',3',4'-ij]-phthalazine in a yield of 88%. Melting point: 242° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][C:22]1[CH2:26][CH2:25][CH2:24][C:23]=1Br.O>C1(C)C(CCO)=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:6]1[CH:5]=[C:4]([C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[Br:21])[CH:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: COC(=O)c1cc(N)cc(B(O)O)c1
Reactant: BrC1=C(Br)CCC1
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1cc(N)cc(C2=C(Br)CCC2)c1
Yield: 86.9 %

Procedure:
(3-amino-5-methoxycarbonylphenyl)boronic acid (2.66 g, 13.6 mmol), Pd(0) [PPh3]4 (1.57 g, 1.36 mmol), potassium carbonate (15 g, 108 mmol) and 1,2-dibromocyclopentene (12 g, 53 mmol) in toluene-ethanol (1:1 60 mL) were stirred at 90° C., under nitrogen, for 2 hrs. Upon cooling, the reaction mixture was poured into water and extracted with ethyl acetate (40×3 mL). The combined organic layers were dried over MgSO4 and concentrated. Purification was carried out on a Biotage® using isohexane containing a gradient of ethyl acetate (0–20%) to give the required product as yellow solid (3.5 g, 87%). 1H NMR (CDCl3):1.96–2.0 (2H,m), 2.50 (2H,t,J=7.4), 2.67 (2H,t,J=7.4), 3.80 (2H,bs), 3.88 (3H,s), 7.14 (1H,s), 7.28 (1H,s), 7.59 (1H,s). LC/MS[MH+]=296, 298 Rt=3.38.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1.[C-:17]#[N:18].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:17]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]=2[CH:16]=1)#[N:18]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc2cc(CCl)ccc2o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(CC#N)ccc2o1
Reaction time: 18 h
Yield: 66.7 %

Procedure:
A mixture of ethyl 5-chloromethylbenzofuran-2-carboxylate (3.0 g, 0.0126 mol), sodium cyanide (1.23 g, 0.025 mol), tetrabutylammonium bromide (0.50 g, 0.0013 mol), water (10 cm3) and dichloromethane (10 cm3) was vigorously stirred for 18 hr. at room temperature. The mixture was separated and the organic layer was washed with water, dried (Na2SO4), filtered and the solvent was removed. The residue was recrystallised from petroleum ether (b.p. 60°-80° C.) to give ethyl 5-cyanomethylbenzofuran-2-carboxylate (1.92 g, 0.0084 mol, 66.6%) m.p. 76°-77° C.-t.l.c./silica/toluene, RF 0.11.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]2[C:29]([O:31][C:32](=O)[C:22]=2[CH:21]=1)=[O:30]>>[C:26]([C:25]1[CH:24]=[C:23]2[C:22](=[CH:21][CH:20]=1)[C:32](=[O:31])[N:1]([C:2]1[CH:3]=[C:4]([C:8]3[O:9][C:10]4[C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)[CH:5]=[CH:6][CH:7]=1)[C:29]2=[O:30])([OH:28])=[O:27]
Reactant: Nc1cccc(-c2nc3cccc(C(=O)O)c3o2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4cccc(C(=O)O)c4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)benzoxazole-7-carboxylic acid (100 mg, 0.39 mmol) and 1,2,4-benzenetricarboxylic anhydride (75 mg, 0.39 mmol) the title compound was obtained, (148 mg, 32%). 1H NMR (DMSO) δ 8.50(m, 2H), 8.39(m, 2H), 8.17(m, 2H), 8.01(m, 1H), 7.88(m, 2H), 7.63(t, 1H). MS 429 m/z (M+H)+.