Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C([O:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:37]2[C:45]3[C:40](=[CH:41][C:42]([C:46](O)=[O:47])=[CH:43][CH:44]=3)[C:39]([CH3:49])=[C:38]2[CH3:50])=[CH:32][CH:31]=1)=[O:23])(C)(C)C>>[CH2:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:46]([C:42]2[CH:41]=[C:40]3[C:45](=[CH:44][CH:43]=2)[N:37]([CH2:36][C:33]2[CH:32]=[CH:31][C:30]([C:25]4[C:24]([C:22]([OH:23])=[O:21])=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:35][CH:34]=2)[C:38]([CH3:50])=[C:39]3[CH3:49])=[O:47])[CH2:3]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H]3CCN(C(=O)OCc4ccccc4)C3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-benzyl 3-aminopyrrolidine-1-carboxylate and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 601 [M+1]+.
Reaction SMILES: C(=O)(O)[O-].[K+].[C:6]1(=[O:19])[O:16]CC[O:13][C:11](=[O:12])[C:10]2[CH:17]=[CH:18][C:7]1=[CH:8][CH:9]=2.C(=O)=O>O>[C:6]([OH:19])(=[O:16])[C:7]1[CH:18]=[CH:17][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C1OCCOC(=O)c2ccc1cc2
Agent: O=C([O-])O
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 190 °C

Procedure:
In a heated autoclave, provided with a mixer and filled partially with water, disintegrated poly/ethyleneterephtalate/ wastes in a form of scraps of bottles and textiles were placed in the amount of 1000 g together with a solution of 1043 g of potassium bicarbonate (KHCO3) in 10 liters of water, and then a content of the reactor was heated up to 190° C. and the temperature was kept till the digestion of poly/ethylene terephtalate/ was completed and the formation of carbon dioxide was stopped. Then the autoclave was relieved and carbon dioxide was separated, and a resulted solution was filtered hot through a filter with active carbon. The filtrate was neutralised with orthophosphoric acid and a precipitate of terephtalic acid was separated from a reaction solution using a centrifuge. The resulted product was washed with a distilled water and crystallised from water, giving 864,2 g of terephtalic acid. At the same time ethylene glycol was separated from the neutralised filtrate using distillation, obtaining 322,5 g of ethylene glycol and almost theoretical amount of inorganic salt.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[CH2:39][C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([NH:30][C:31]2[C:32]3[C:39](=[CH:20][C:3]4[NH:4][C:5]5[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]6[CH2:14][CH2:15][O:16][CH2:17][CH2:18]6)[C:7](=[O:19])[C:6]=5[C:2]=4[CH3:1])[C:38](=[O:40])[NH:37][C:33]=3[N:34]=[CH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 37.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]-pyrimidin-6-one as starting materials to give 4-(3-chloro-4-fluoro-phenylamino)-5-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (33 mg, 37.9%) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[NH:12][CH:13]=[CH:14][CH:15]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[NH:12][CH:13]=[CH:14][CH:15]=4)[C:5]3=[CH:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: Clc1ccc2c(-c3ccc[nH]3)n[nH]c2n1
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc3c(-c4ccc[nH]4)n[nH]c3n2)CC1

Procedure:
6-chloro-3-(1H-pyrrol-2-yl)-1H-pyrazolo-[3,4,b]-pyridine (Example 9) and N-methyl piperazine using the same metho in Example 36.
Reaction SMILES: CON(C)[C:4](=[O:9])[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][Mg]Cl>>[CH3:7][CH:6]([CH3:8])[CH2:5][C:4](=[O:9])[CH2:11][C:12]1[CH:13]=[C:14]([CH3:15])[CH:18]=[CH:19][CH:20]=1
Reactant: CON(C)C(=O)CC(C)C
Reactant: Cc1cccc(C[Mg]Cl)c1
Product: Cc1cccc(CC(=O)CC(C)C)c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 36-b) using N-methoxy-N-methyl-3-methylbutanamide and 3-methylbenzyl magnesium chloride to obtain a title compound as a light yellow oily substance.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:6])=[O:5].Cl[CH2:20][CH2:21][CH2:22][CH:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>C1C=CC=CC=1.CN(C)C=O>[C:30]([O:29][CH:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21][CH2:20][N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:4]([CH3:3])(=[O:6])=[O:5])(=[O:32])[CH3:31]
Reactant: CCCCCC(CCCCl)OC(C)=O
Reactant: CCOC(=O)CCCCCCNS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(C)(=O)=O)OC(C)=O
Temperature: 25 °C

Procedure:
Sodium hydride (0.715 g., 0.0298 mole) is suspended in benzene (30 ml.) and dimethylformamide (30 ml.). Ethyl 7-(methanesulfonamido)heptanoate (6.8 g., 0.0271 mole) (Example O, Step 1) is added and the suspension heated on the steam bath for 15 minutes. After cooling to room temperature, 1-chloro-4-acetoxynonane (6.55 g., 0.0298 mole) (Example A, Step 3) is added over 15 minutes and the resulting solution heated on the steam bath for 20 hours. Then the reaction is poured into water (300 ml.) and extracted with ethyl acetate (3× 100 ml.). The organic layer is washed with brine (2× 50 ml.), dried over sodium sulfate then concentrated in vacuo to an oil which is purified by chromatography on silica gel. The silica gel is eluted with 3% methanol in chloroform and evaporation of the appropriate fraction affords ethyl 7-[N-(4-acetoxynonyl)methanesulfonamido]heptanoate. The yield is 6.0 g. (51%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:21](=[O:22])[C:20]3=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]3[C:18]2=[O:27])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[CH2:29]([O:36][NH:37][C:14](=[O:15])[CH2:13][CH:12]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[N:17]1[C:18](=[O:27])[C:19]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:20]2[C:21]1=[O:22])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OC
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NOCc2ccccc2)N2C(=O)c3ccccc3C2=O)ccc1OC
Yield: 93.8 %

Procedure:
N-Benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-phthalimido-propanoic acid (869 mg, 2.36 mmol), N,N′-carbonyldiimidazole (410 mg, 2.53 mmol) and O-benzylhydroxylamine hydrochloride (444 mg, 2.78 mmol) in tetrahydrofuran (6 mL) to afford N-benzyloxy-3-(3-ethoxy-4-methoxyphenyl)-3-phthalimidopropionamide as a white solid (1.05 g, 94% yield): mp, 165.0-166.0° C.; 1H NMR (CDCl3) δ1.44 (t, J=7.0 Hz, 3H, CH3), 2.95 (dd, J=5.8, 14.0 Hz, 1H, CHH), 3.49 (t, J=12.1 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.07 (q, J=7.0 Hz, 2H, CH2), 4.77 (br s, 2H, PhCH2), 5.83 (dd, J=6.0, 10.0 Hz, 1H, NCH), 6.79 (d, J=8.0 Hz, 1H, Ar), 7.06-7.09 (m, 2H, Ar), 7.25-7.85 (m, 5H, Ar), 7.66-7.71 & 7.74-7.79 (2ms, 4H, Ar), 8.34 (br s, 1H, NH); 13C NMR (CDCl3) δ14.68, 35.66, 51.54, 55.88, 64.34, 78.13, 111.32, 12.52, 120.08, 123.29, 128.52, 128.67, 129.06, 131.26, 131.76, 133.98, 134.98, 148.31, 149.15, 167.38, 168.26. Anal. Calcd for C27H26N2O6: C, 68.34; H, 5.52; N, 5.90. Found: C, 68.36; H, 5.47; N, 5.74.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].C([O-])(O)=O.[Na+].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[O:18]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:11][N:2]1[NH:1][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nn1nc(-c2ccccc2)c2ccccc2c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nn1nc(-c2ccccc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The general procedures described in Example 14, parts A and B are followed. The obtained 2-amino-4-phenyl-(2H)-1-phthalazinone (0.01 mol) is stirred with aqueous NaHCO3 and benzoylchloride (0.01 mol) in dichloromethane at room temperature overnight. The organic phase is washed with water, dried over Na2SO4 and dichloromethane is evaporated. The product is recrystallized to yield the title compound, N-(1-oxo-4-phenyl-(2H)-phthalazin-2-yl)benzamide (R1=benzyl, Y1=NH—C(O), R2=phenyl, A=phenyl, m=0, p=0).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:23][C:24]1[C:29]([CH:30]=O)=[CH:28][N:27]=[C:26]([CH3:32])[C:25]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[CH:51][CH:50]=2)=[CH:45][CH:44]=1>>[CH2:1]([O:8][C:9](=[O:41])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:23][C:24]1[C:29]([CH2:30][NH:42][C:43]2[CH:44]=[CH:45][C:46]([C:49]3[CH:54]=[CH:53][C:52]([C:55]#[N:56])=[CH:51][CH:50]=3)=[CH:47][CH:48]=2)=[CH:28][N:27]=[C:26]([CH3:32])[C:25]=1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1ncc(C=O)c(CN(CCCCCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1OCc1ccccc1
Product: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2)c(CN(CCCCCC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)c1OCc1ccccc1
Yield: 83.3 %

Procedure:
The reductive amination of 6-[(3-benzyloxy-5-formyl-2-methyl-pyridin-4-ylmethyl)-tert-butoxycarbonyl-amino]-hexanoic acid benzyl ester (2.2 g, 3.9 mmol) and 4-amino-4′-cyanobiphenyl (2.1 g, 10.8 mmol), as described in Example 21, gave 6-({3-benzyloxy-5-[(4′-cyano-biphenyl-4-ylamino)-methyl]-2-methyl-pyridin-4-ylmethyl}-tert-butoxycarbonyl-amino)-hexanoic acid benzyl ester (44) (2.4 g, 83% yield).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(N(CC)CC)C.[CH3:19][Si:20]([CH3:23])([CH3:22])Cl>C(#N)C>[CH3:19][Si:20]([CH3:23])([CH3:22])[N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1NC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)N1C(=O)c2ccccc2C1=O

Procedure:
250 g (1.7 moles) of phthalimide were suspended in 2.75 liter of acetonitrile and after 250 ml (1.8 moles) of triethylamine were added, the mixture was heated to gentle reflux 250 ml (1.97 moles) of trimethylchlorosilane were added in 10 minutes and the reaction mixture was then concentrated to a thick paste. 2.5 liter of light petroleum (80°-110° C) were added, the triethylammonium hydrochloride was filtered off and washed with 500 ml of light petroleum. The filtrate and washings were combined and concentrated until crystallization started. After cooling in the refrigerator for several hours, N-trimethylsilylphthalimide was isolated by filtration, washed with a small portion of light petroleum (40°-60° C) and dried in vacuo. The compound was further purified by recrystallization from ligroin (80°-100° C).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10](C1C=CC=CC=1C)[C:11]([OH:13])=[O:12].[NH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24]>O(CC)CC>[NH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([NH:21][C:25]1[CH:26]=[CH:4][CH:3]=[CH:2][C:7]=1[CH3:6])[C:11]([OH:13])=[O:12]
Reactant: Cc1ccccc1C(C(=O)O)c1c(Cl)ccc(Cl)c1Cl
Solvent: OCCNCCO
Solvent: CCOCC
Product: Cc1ccccc1NC(C(=O)O)c1c(Cl)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 8.62 parts of 2,3,6-trichloro-α-(2-methylphenyl)benzeneacetic acid in 175 parts of 1,1'-oxy-bisethane are added 2.62 parts of 2,2'-iminobis[ethanol] and the whole is stirred for 1 hour at room temperature. The precipitated product is filtered off and stirred in 70 parts of 1,1'-oxybisethane. It is filtered off again and dried, yielding 10 parts of 2,3,6-trichloro-α-[(2-methylphenyl)amino]benzeneacetic acid compound with 2,2'-iminobis[ethanol] (1:1); mp. 145.2° C.
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[N+](=[CH2:24])=[N-]>ClCCl>[CH:1]([C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH3:24])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=[N+]=[N-]
Reactant: C=Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1
Solvent: ClCCl
Product: C=Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)OC)cc1
Temperature: 25 °C

Procedure:
A solution of 200 mg of 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-(4-vinylbenzoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate. Likewise but using diazoethane, diazopropane and diazobutane in place of diazomethane there are respectively obtained:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Zn]I)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>C1COCC1.Cl[Pd](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1([C:17]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1ccc([Zn]I)cc1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC2)cc1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
(4-Ethoxycarbonylphenyl)-iodo-zinc (20 mL of 0.5 M in THF, 10.0 mmol) was added over 10 min to dichloro-bis(triphenylphosphoranyl)palladium (211 mg, 0.3 mmol) in THF (20 mL) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes, cyclopropanecarbonyl chloride (941 mg, 817 μL, 9.0 mmol) was added dropwise at 0° C. and stirred for 2 hours. The reaction mixture was quenched with 1M HCl (20 mL), extracted with ethyl acetate (2×50 mL). The organic layer was washed sequentially with sat. aq. NaHCO3 (5 mL) and brine solution (50 mL), dried over MgSO4 and purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give ethyl 4-(cyclopropanecarbonyl)benzoate (1.54 g, 71%) as a pale yellow oil. ESI-MS m/z calc. 218.0. Found 219.3 (M+1)+; Retention time: 1.57 minutes (3 min run).
Reaction SMILES: [Na].[CH:2]([C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[N:16]=[CH:17]3)=[CH:12][CH:11]=2)=[C:6]([CH3:26])[CH:5]=1)=[O:3]>O1CCCC1>[OH:3][CH2:2][C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([NH:20][C:21]([CH:23]4[CH2:25][CH2:24]4)=[O:22])[N:16]=[CH:17]3)=[CH:12][CH:11]=2)=[C:6]([CH3:26])[CH:5]=1
Reactant: Cc1cc(C=O)ncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(CO)ncc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
Sodium tertrahydroborate (10 mg, 0.27 mmol) was added to a solution of N-(7-(6-formyl-4-methylpyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (45 mg, 0.14 mmol) in tetrahydrofuran (0.8 mL) cooled at 0° C. After 15 minutes, the reaction mixture was quenched with a few drops of water, diluted ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% formic acid over 14 min) to afford the title compound as an off-white solid (26 mg, 60%). 1H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 9.14 (s, 1H), 8.51 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 7.94 (m, 2H), 7.56 (d, J=8.5 Hz, 1H), 7.33 (d, J=5.0 Hz, 1H), 4.85 (t, J=5.3 Hz, 1H), 4.25 (d, J=5.2 Hz, 2H), 2.08 (m, 4H), 0.85 (m, 4H). LCMS (Method H): RT=2.40 min, M+H+=334.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccnc(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (33 mg, 41%), MS (ISP) m/z=321.4 [(M+H)+], mp 256° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](O)=[O:5].CC(C)=CCO.S(Cl)(Cl)=O.[O-][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>C1C=CC=CC=1>[CH3:1][C:2]([CH3:7])=[CH:3][CH2:4][O:5][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [O-]c1ccccc1
Reactant: CC(C)=CC(=O)O
Agent: CC(C)=CCO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C)=CCOc1ccccc1

Procedure:
3,3-dimethylallylphenyl ether was prepared from 3,3-dimethylacrylic acid by reduction with sodium dihydro-bis (2-methoxyethoxy) aluminate in benzene, chlorination of the resulting 3,3-dimethylallyl alcohol with thionyl chloride and reaction of the product with sodium phenoxide in the presence of a polar solvent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][C@@H:48]([NH2:50])[CH3:49])[C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][C@@H:48]([NH:50][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:49])[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1ccc(OC[C@H](C)N)c(Cl)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (513 mg, 1.07 mmol), methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate (260 mg, 1.07 mmol) and Et3 N (220 μl, 1.58 mmol) in DMF (10 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc and the solution was washed with sat. NaHCO3, dried over Na2SO4, and evaporated. The residue was recrystallized from MeOH—CHCl3-EtOAc-n-hexane to give 400 mg (69%) methyl (S)-3-chloro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as pale brown crystalline powder. 1H-NMR (DMSO-d6) δ 1.21 (d, 3 H, J=6.4 Hz), 2.24 (s, 3 H), 3.37 (s, 2 H), 3.82(s, 3 H), 3.83 (s, 3 H), 4.04–4.12 (m, 3 H), 6.75–6.77 (m, 1 H), 6.91–6.95 (m, 2 H), 7.11–7.17 (m, 2 H), 7.29–7.31 (m, 1 H), 7.78–7.99 (m, 4 H), 8.12–8.13 (m, 1H), 8.46 (s, 1 H), 8.55 (s, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:12]=1.B(Br)(Br)Br.C1CCCCC=1>>[CH2:24]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[C:11]([C:4]2[CH:5]=[CH:6][C:7]([OH:9])=[CH:8][C:3]=2[OH:2])=[N:12]1)[CH:25]([CH3:27])[CH3:26]
Reactant: COc1ccc(-c2nn(CC(C)C)c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CC(C)Cn1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Yield: 49.5 %

Procedure:
Prepared according to Method D step C from 3-(2,4-dimethoxyphenyl)-1-isobutyl-7-(trifluoromethyl)-1H-indazole (0.675 g, 1.2 mmol), boron tribromide (1.01 mL, 10.7 mmol) and 1.0 mL of cyclohexene to give the product (0.208 g) as an off-white solid.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:4]=[N:3][N:2]1[C:10](=[N:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([NH:24]C(=O)C)=[CH:20][CH:19]=1)(=[O:17])=[O:16])[NH:11][CH2:12][CH3:13].Cl>CCO>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([S:15]([N:14]=[C:10]([N:2]2[N:3]=[CH:4][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:1]2)[NH:11][CH2:12][CH3:13])(=[O:17])=[O:16])=[CH:23][CH:22]=1
Reactant: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)cc1)N1CC2(C=N1)CCCC2
Agent: Cl
Solvent: CCO
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCCC2
Temperature: 55 °C
Reaction time: 45 h
Yield: 55 %

Procedure:
179 g N-(4-{[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]sulfamoyl}-phenyl)acetamide was dissolved in 2685 mL EtOH, and 1370 mL of 1M HCl (3 mol equiv.) was added. The mixture was stirred at 55° C. for 45 h. and concentrated under reduced pressure. The residue was taken up in 2200 mL butyl acetate, and 3800 mL of 5% aqueous NaHCO3 was dosed over a period of 55 minutes under stirring. The organic phase was separated and the aqueous phase was extracted with 200 mL butyl actetate. The combined organic layers were washed with 1300 mL water and evaporated to dryness to give 133 g of crude material. The residue was recrystallized from 800 mL of EtOH and dried in vacuo at 50° C. to give 87.8 g (55%) of 4-amino-N-[(2,3-diaza-spiro[4.4]non-3-en-2-yl)-ethylamino-methylene]-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7.22 Hz, 3H), 1.47-1.89 (m, 8H), 3.35-3.57 (m, 2H), 3.79 (s, 2H), 4.02 (br.s., 2H), 6.65 (d, J=8.73 Hz, 2H), 6.78 (s, 1H), 6.91 (br. s., 1H), 7.70 (d, J=8.73 Hz, 2H).