Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1S[C:4]2C=C(OC)C=C[C:5]=2N=1.BrC1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1.CO[C:31]1[CH:46]=[CH:45][C:34]2[N:35]=[C:36]([C:38]3[CH:39]=[N:40][C:41](N)=[N:42][CH:43]=3)[S:37][C:33]=2[CH:32]=1>>[S:37]1[C:33]2[CH:32]=[CH:31][CH:46]=[CH:45][C:34]=2[N:35]=[C:36]1[C:38]1[CH:4]=[CH:5][C:41]([NH:42][CH3:43])=[N:40][CH:39]=1
Reactant: COc1ccc2nc(Br)sc2c1
Reactant: COc1ccc2nc(-c3cnc(N)nc3)sc2c1
Agent: CC1(C)OB(c2ccc(Br)nc2)OC1(C)C
Product: CNc1ccc(-c2nc3ccccc3s2)cn1
Reaction time: 2 h

Procedure:
2-Bromo-6-methoxy-1,3-benzothiazole (49 mg, 0.20 mmol) and 2-bromo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68 mg, 0.24 mmol) were reacted according to the procedure used for the preparation of 5-(6-methoxy-1,3-benzothiazol-2-yl)pyrimidin-2-amine, with the following exceptions: The reaction was stirred for 2 h and was then allowed to reach rt on. The mixture was filtered through a plug of silica and Na2SO4, eluting with DCM. The volume of the filtrate was reduced in a centrifuge and the remainder was purified by HPLC to give the title compound (4.2 mg). 1H NMR (CHLOROFORM-d: CD3OD) δ 8.93 (d, 1 H) 8.21 (dd, 1 H) 7.92 (d, 1 H) 7.68 (d, 1 H) 7.43 (d, 1 H) 7.12 (dd, 1 H) 3.89 (s, 3 H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][NH:23]3)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].Cl>CO.O>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[CH:22][NH:23]4)[CH:13]=[N:12]2)[C:3]([OH:28])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (500 mg, 1.3 mmol) in methanol (3 mL) was treated with a 4N aqueous sodium hydroxide solution (63 mg, 1.57 mmol). The reaction solution was stirred at 25° C. overnight. At this time, the reaction mixture was diluted with water (10 mL) and was acidified with a 1N aqueous hydrochloric acid solution until pH=2. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organics were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Chromatography afforded 3-cyclopentyl-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as an off-white solid (0.2 g, 42%); LC-MS: 368 [M+1]+, tR=4.21 min. Purity on HPLC: 95.1% (254 nm), 96.6% (214 nm), tR=7.26 min. 1H NMR (300 MHz, CDCl3): δ 13.00 (s, 1H), 11.50 (s, 1H), 8.17 (d, 1H, J=2.4 Hz), 7.42 (d, 2H, J=7.8 Hz), 7.17 (t, 1H, J=7.8 Hz), 6.89 (d, 1H, J=7.8 Hz), 6.26 (s, 1H), 5.63 (d, 1H, J=2.4 Hz), 5.31 (dd, 1H, J1=10.5 Hz, J2=4.2 Hz), 2.23˜2.13 (m, 1H), 2.02˜1.94 (m, 1H), 1.59˜1.44 (m, 7H), 1.18˜1.04 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22]O)[C:11](=[O:26])[C@H:10]([CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][NH:34][S:35]([CH:38]1[CH2:40][CH2:39]1)(=[O:37])=[O:36].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCOC(C)=O.[Na+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:34]([CH3:33])[S:35]([CH:38]3[CH2:40][CH2:39]3)(=[O:37])=[O:36])[C:11](=[O:26])[C@H:10]([CH:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CO)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CNS(=O)(=O)C1CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
A flask, containing a solution of methyl 2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)propanoate (195 mg, 0.408 mmol; Example 127, Step E) and N-methylcyclopropanesulfonamide (165 mg, 1.223 mmol) in toluene (2038 μL) was evacuated and backfilled with Ar (5×). Then cyanomethylenetributylphosphorane (321 μL, 1.223 mmol) was added. The light brownish orange mixture was heated to 70° C. for 2 h. More N-methylcyclopropanesulfonamide (134 mg, 0.991 mmol) was added and the mixture was heated to 70° C. for 2 h. The mixture was heated to reflux overnight and then cooled to room temperature. The mixture was diluted with EtOAc and sat. aq. NaCl solution. The layers were separated. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (4 g column eluent: 0 to 100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:11][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2ccc(Br)cc2C(C)=O)cc1

Procedure:
5′-bromo-2′-hydroxyacetophenone (compound 12) (1.80 g, 10.6 mmol) was added to a pyridine solution (40 ml) that contained 4-methoxybenzoyl chloride (2.01 g, 9.35 mmol) in an ice bath. The obtained mixture was reacted at room temperature for 30 minutes, and the reaction solution was then poured into 1 N hydrochloric acid under cooling on ice. The obtained mixture was intensively stirred. The obtained precipitate was collected by filtration, and the filtrate was then washed with purified water, so as to obtain a product of interest, 4-methoxybenzoic acid 2-acetyl-4-bromophenyl ester (compound 13). Yield: 3.15 g (yield constant: 96.5%) 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 8.86 (s, 1H), 10.13 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]2[C:12](=[O:13])[NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([N:16]([CH2:19][CH2:20]Cl)[CH2:17][CH3:18])[CH3:15].C(N(CC)CC)C>CC(C)=O>[CH2:14]([N:16]([CH2:19][CH3:20])[CH:17]([N:8]1[CH2:9][CH2:10][NH:11][C:12](=[O:13])[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:18])[CH3:15]
Reactant: O=C1NCCNC1c1ccccc1
Reactant: CCN(CC)CCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCN(CC)C(C)N1CCNC(=O)C1c1ccccc1
Yield: 64 %

Procedure:
144 g. of 2-phenyl-3-keto piperazine are boiled under reflux with 121 g. of diethylamino ethylchloride, 340 cc. of triethylamine, and 1600 cc. of acetone for 24 hours. The cooled solution is filtered to remove triethylamine hydrochloride and the filtrate is evaporated to dryness. The residue is dissolved in water, 40 % sodium hydroxide solution is added thereto, and the oil which forms an upper layer, is extracted with benzene. The benzene solution is dried over anhydrous potassium carbonate, the benzene is removed by distillation, and the residue is distilled in a vacuum. A light yellow, viscous oil of the boiling point 175° C./0.05 mm. Hg is obtained. The oil is twice recrystallized from n-heptane. 145 g. of the above mentioned compound melting at 53°-56° C. are obtained.. The yield is 64 % of the theoretical yield.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:23])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])=[O:13])[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>C(O)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][CH2:2][CH:3]([OH:23])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])=[O:13])[CH2:7][CH2:6]1
Reactant: Clc1nc2ccccc2s1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CN)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)CNc2nc3ccccc3s2)CC1

Procedure:
To a solution of compound 37 (75 mg) in ethanol (2 mL) was added triethylamine (0.13 mL) and 2-chlorobenzthiazole (87 mg) followed by warming to reflux for 16 h. The reaction mixture was concentrated and purified by preparative TLC (5%MeOH/Dichloromethane) to give Compound 39 as a white solid. Mass Spectrum (MH+)=454.4.
Reaction SMILES: [NH2:1][C:2]([CH3:7])=[CH:3][N+:4]([O-:6])=[O:5].[Cl:8][C:9]([C:20](=O)[CH3:21])=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1>C(O)C>[Cl:8][C:9]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:3]([N+:4]([O-:6])=[O:5])=[C:2]([CH3:7])[NH:1][C:20]=1[CH3:21]
Reactant: CC(N)=C[N+](=O)[O-]
Reactant: CC(=O)C(Cl)=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CC1=C(Cl)C(c2cccc([N+](=O)[O-])c2)C([N+](=O)[O-])=C(C)N1

Procedure:
0.1 mol of 2-amino-1-nitro-prop-1-ene and 0.1 mol of 2-chloro-1-(3-nitrophenyl)-but-1-ene-3-one were heated in boiling ethanol, analogously to Example 18. 3-Chloro-1,4-dihydro-2,6-dimethyl-5-nitro-4-(3-nitrophenyl)pyridine of melting point 198° C. (decomposition) was obtained. Yield:
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH:9]=O.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH:9]=[N:26][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:17]
Reactant: NCCc1ccccc1
Reactant: COc1ccc(OCCCN(C)C)c(C=O)c1
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN(C)C)c(C=NCCc2ccccc2)c1
Yield: 83 %

Procedure:
2-[3-(Dimethylamino)propoxy]-5-methoxybenzaldehyde (33.5 g) and 17.4 g of phenethylamine are reacted in 140 ml of toluene following the procedure described in Example 1B yielding 39.9 g of the title compound, boiling point 197°-202° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[C:27][C:2]3[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:12])[CH:3]=3)=[N:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Reactant: Cc1cc(I)ccc1OCCO
Product: Cc1cc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)ccc1OCCO

Procedure:
The product was obtained analogously to Example 7.1e starting from 2-(4-iodo-2-methylphenoxy)ethanol and 5-(4-chlorophenyl)-2-ethynyl-3-fluoropyridine. Yield: 1.40 g (68% of theoretical); C22H17ClFNO2 (M=381.827); calc.: molpeak (M+H)+: 382/384 (Cl); found: molpeak (M+H)+: 382/384 (Cl); HPLC-MS: 6.29 minutes (method B).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[CH:34]1([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(Cl)Cl>[CH:34]1([NH:40][C:10]([NH:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:11])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: NC1CCCCC1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: ClCCl
Product: C=C(C)C(=O)OCCNC(=O)NC1CCCCC1

Procedure:
A 3-neck, 250-mL round bottom flask equipped with a reflux condenser was charged with isocyanatoethyl methacrylate (7.79 g), 1,1'-bi-2-naphthol (1.3 mg) and 50 mL of methylene chloride. While stirring, cyclohexylamine (5.24 g) and dibutyltin dilaurate (52.3 mg) in 50 mL of methylene chloride were added over a 15 minute period. The reaction mixture was kept stirred for an additional 30 minutes. The solution was filtered and evaporated to dryness to recover the product. The product was characterized by H-NMR, 0.72- 2.10 ppm (m, 1H), 1.90 ppm (s, 3H), 3.45 ppm (t, 2H), 3.50 ppm (hidden, 1H), 4.18 ppm (t, 2H), 5.12 ppm (s, 1H), 5.26 ppm (s, 1H), 5.52 ppm (s, 1H), 6.10 ppm (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH2:12]Cl)[CH2:6]1.[K].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH2:12][N:23]2[C:22](=[O:24])[C:21]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]3[C:19]2=[O:29])[CH2:6]1
Reactant: CC1CN(Cc2ccccc2Cl)CC(CCl)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccccc2Cl)CC(CN2C(=O)c3ccccc3C2=O)O1
Temperature: 150 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
A mixture of 4-(2-chlorobenzyl)-2-chloromethyl-6-methylmorpholine (19.7 g), phthalimide potassium salt (14.6 g), and dimethylformamide (150 ml) is stirred at 150° C. for 5 hours. The reaction mixture is poured into ice-water and extracted with diethyl ether. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent is distilled off to give the title compound (26 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(Oc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, phenol and DBU in DME. ES-MS m/e (%): 333 (M+H+, 100).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1([C:18]([O:20]CC)=[O:19])[CH2:17][CH2:16]1)=[O:14]>C(O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:13]([C:15]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]1)=[O:14]
Reactant: CCOC(=O)C1(C(=O)Nc2cc(Cl)c(Cl)cc2C)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(Cl)c(Cl)cc1NC(=O)C1(C(=O)O)CC1
Temperature: 0 °C

Procedure:
A solution containing 0.34 gram (0.006 mole) of potassium hydroxide and 0.109 gram (0.006 mole) of water in 80 milliliters of ethanol was prepared in a 250 milliliter round bottom flask. With cooling to a temperature of 0° C. in an ice/NaCl bath and stirring, a solution of ethyl 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylate prepared in Example III in a small volume of ethanol was added and the mixture allowed to stir with warming to room temperature over a 72 hour period. The mixture was vacuum evaporated to give a white solid residue which was dissolved in water and extracted twice with ether. The ether extracts were discarded. The water solution was acidified to a pH of 2 with 25% Hcl solution causing separation of a solid which was taken up into ether, and the acidified aqueous phase was extracted four times. The combined ether extracts were dried over magnesium sulfate and vacuum evaporated to give a white solid. This white solid was water-washed and dried in a vacuum oven to give 1.85 grams (0.006 mole) of 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylic acid having a melting point of 248° C.-251° C.
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])[CH2:9][N:8]([C:15](Cl)=[O:16])[CH2:7][CH2:6]2.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(=O)C1C=CC=CC=1>>[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:15]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:9]1)=[O:16]
Reactant: O=C(NCCCCO)c1ccccc1
Reactant: COc1cc2c(cc1OC)CN(C(=O)Cl)CC2
Product: COc1cc2c(cc1OC)CN(C(=O)NCCCCO)CC2
Yield: 67 %

Procedure:
6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (4-hydroxy-butyl)-amide (25B) is prepared from 25A as described for 1D.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[N+:2]=[N-:3].Cl.[CH3:15][CH2:16][OH:17]>>[N:1]([CH2:4][CH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10](=[NH:11])[O:17][CH2:16][CH3:15])=[CH:8][CH:7]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1ccc(CCN=[N+]=[N-])cc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(CCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(2-azidoethyl)benzonitrile (2.0 g, 11.62 mmol) in EtOH (50 ml) at 0° C. was saturated with HCl(g). Reaction mixture was allowed to warm to room temperature and stirred overnight. Concentration of the crude reaction mixture gave ethyl 4-(2-azidoethyl)benzenecarboximidoate which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[CH:7](O)[CH:6]([CH2:13][CH:14]([CH2:20][OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:5]2.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.FC1C=C2C(=CC=1F)C1OCC(CCCCC)CC1C2>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[C@@H:7]1[O:21][CH2:20][C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][C@H:6]1[CH2:5]2
Reactant: CCCCCC(CO)CC1Cc2cc(F)c(F)cc2C1O
Agent: CCCCCC1COC2c3cc(F)c(F)cc3CC2C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC[C@H]1CO[C@H]2c3cc(F)c(F)cc3C[C@@H]2C1
Reaction time: 8 h

Procedure:
6.0 g (21.4 mmol) of 5,6-difluoro-2-(2-hydroxymethylheptyl)indan-1-ol are dissolved in 70 ml of dichloromethane and 10 ml of pyridine, and 9.5 g (50 mmol) of p-toluenesulfonyl chloride are added with ice-cooling. The cooling is removed, and the batch is left to stir at room temp. overnight. After addition of 100 ml of dichloromethane, the solution is washed three times with 2 N hydrochloric acid and once each with water and copper sulfate solution and dried over sodium sulfate. The solvent is removed in vacuo, giving an isomer mixture of 7,8-difluoro-3-pentyl-2,3,4,4a,5,9b-hexahydroindeno[1,2-b]pyran, which is separated by chromatography on silica gel (eluent heptane/toluene 5:1), giving the racemate of (3R*,4aS*,9bR*)-7,8-difluoro-2,3,4,4a,5,9b-hexahydro-3-pentylindeno[1,2-b]pyran and the enantiomer thereof as a colourless solid; Δ∈=13.4; Δn=0.1021.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[C:24]([CH2:26][CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])#[N:25]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][N:28]([CH2:27][CH2:26][C:24]#[N:25])[CH2:29][C:30]([OH:32])=[O:31])[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: N#CCCNCC(=O)O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(CCC#N)CC(=O)O

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with N-(2-cyanoethyl)glycine using an analogous method to that described for the equivalent step in Example 1 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-cyanoethyl)glycine; 1H NMR Spectrum: (DMSO-d6) 2.70 (t, 2H); 3.04 (t, 2H); 3.40 (s, 2H); 3.95 (m, 5H); 7.20 (s, 1H); 7.27 (t, 1H); 7.48 (t, 1H); 7.55 (t, 1H); 8.36 (s, 1H); 8.44 (s, 1H); 9.69 (brs, 1H); Mass Spectrum: (M+H)+ 444.
Reaction SMILES: N#N.[NH2:3][CH2:4][C:5]([OH:7])=O.[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)C(=O)[O:15][C:16](=O)[C:11]=2[CH:10]=1>CC(O)=O>[Cl:8][C:9]1[CH:29]=[CH:28][C:12]2[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:5](=[O:7])[CH2:4][NH:3][C:16](=[O:15])[C:11]=2[CH:10]=1
Reactant: NCC(=O)O
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3cc(Cl)ccc32)cc1
Agent: N#N
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)CNC(=O)c3cc(Cl)ccc32)cc1
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
In a 2 L RBF equipped with mechanical stir, condenser and N2 inlet, glycine (34 g, 0.45 mol) was added to 6-chloro-1-(4-methoxybenzyl)-1H-benzo[d][1,3]oxazine-2,4-dione (280 g) followed by the addition of AcOH (500 mL). Reaction flask was heated in a 130° C. oil bath for 8 h. Solvent was removed on the rotary evaporator at 50-60° C. To the thick syrupy crude product was added heptane (1 L) and H2O (1 L) followed by the addition of NaHCO3 to adjust the pH to ˜8-9. The mixture gave a solid along with organic and aqueous layers. The organic and aqueous layers were decanted and the solid was slurried with 500 mL of 5% NaHCO3 solution. NaHCO3 layer was decant and sticky solid was suspended in 700 mL EtOAc and 300 mL of dichloromethane (DCM). The mixture was stirred for 20 min, filtered and the filter cake was washed with 1 L of DCM. The filtrate was concentrated and residue was pass through 330 g silica gel plug using 25/75 to 75/25 EtOAC/heptane (total of 8 L). Clean fractions were combined to give 58 g of pure product. An additional 13 g of ˜70% pure product was obtained from less pure fractions. Yield was 47% over two steps. 1H NMR (300 MHz, DMSO-d6) δ 3.45 (m, 1H), 3.6 (s, 3H), 3.8 (m, 1H), 4.8 (d, 1H), 5.3 (d, 1H), 6.8 (d, 2 H), 7.1 (d, 2H), 7.7-7.5 (m, 3H), 8.9 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][C:23]1[N:24]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[C:25]([CH3:28])=[CH:26][CH:27]=1>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([N:24]5[C:25]([CH3:28])=[CH:26][CH:27]=[C:23]5[CH3:22])[CH:30]=4)[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C)n1-c1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(-n3c(C)ccc3C)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 3-(2,5-dimethylpyrrol-1-yl)benzoic acid (122 mg, 0.57 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue chromatographed on a silica gel flash column eluting with ethyl acetate/hexane (1:1) and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-3-(2,5-dimethylpyrrol1-yl)benzamide (75 mg, 74%). NMR; δH CDCl3 7.91,(1H, d), 7.83,(2H, d), 7.79,(1H, s), 7.71,(1H, s), 7.61-7.55,(2H, m), 7.49,(1H, s), 7.41,(3H, m), 7.29,(1H, d), 6.24,(1H, m), 5.92,(2H, s), 3.34,(2H, m), 2.23,(3H, s), 2.04,(6H, s), 1.08,(1H, m), 0.57,(2H, m), 0.29,(2H, m). LCMS: retention time 3.80 min, MH+478.