Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=O)[CH:8]=2)[O:3]1.[CH3:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][C:19](=[O:25])[NH:20]2>>[CH3:1][C:2]1([CH3:14])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]=[C:18]3[C:17]4[C:21](=[CH:22][CH:23]=[CH:24][C:16]=4[CH3:15])[NH:20][C:19]3=[O:25])[CH:8]=2)[O:3]1
Reactant: Cc1cccc2c1CC(=O)N2
Reactant: CC1(C)CCc2cc(C=O)ccc2O1
Product: Cc1cccc2c1C(=Cc1ccc3c(c1)CCC(C)(C)O3)C(=O)N2

Procedure:
2,2-Dimethyl-6-formylchromane (commercially available) was condensed with 4-methyl-2-oxindole to give 0.25 g of 3-(2,2-dimethylchroman-6-ylmethylene)-4-methyl-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]([OH:29])[C@H:21]1[O:26][C:24](=[O:25])[C:23]([OH:27])=[C:22]1[OH:28])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:30](Cl)(=[O:36])/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH3:35]>N1C=CC=CC=1.ClCCl>[C:1]([O:18][CH2:19][C@H:20]([OH:29])[C@H:21]1[O:26][C:24](=[O:25])[C:23]([O:27][C:30](=[O:36])/[CH:31]=[CH:32]/[CH:33]=[CH:34]/[CH3:35])=[C:22]1[OH:28])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C/C=C/C=C/C(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C/C=C/C=C/C(=O)OC1=C(O)[C@@H]([C@@H](O)COC(=O)CCCCCCCCCCCCCCC)OC1=O
Reaction time: 2 h

Procedure:
50 g (120 mmol; 1 eq.) of 6-O-palmitoyl-L-ascorbic acid were dissolved in 400 ml of pyridine in a 1 l 4-necked flask. 23.40 g (130 mmol; 1.1 eq.) of sorboyl chloride, dissolved in 30 ml of dichloromethane, were slowly added dropwise at an internal temperature of -15° C. Care was taken here that the internal temperature did not exceed -10° C. The mixture was brought to room temperature and additionally stirred for 2 hours. The reaction solution was concentrated on a rotary evaporator and then codistilled with toluene. The residue was taken up in a little dichloromethane and extracted with 1 M HCl. The organic phase was concentrated somewhat and treated with an excess of n-hexane. A white precipitate was deposited, which was dried in an oil pump vacuum.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
64 mg (93%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (46 mg, 0.166 mmol), 1-(4-methoxyphenyl)piperazine (40 mg, 0.151 mmol), DIPEA (0.026 mL, 0.151 mmol) and NaBH(OAc)3 (96 mg, 0.453 mmol).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([C:7]1[C:8](=[C:15]([C:18]#[N:19])[C:16]#[N:17])[O:9][C:10]([CH3:14])([CH3:13])[C:11]=1[CH3:12])#[N:6].[C:20]([SiH2:24][O:25][C:26]([CH3:52])([CH3:51])[CH:27]1[CH2:32][O:31][C:30]2=[C:33]([CH:38]=[CH:39][C:40]3[CH:45]=[CH:44][C:43]([N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])=[CH:42][CH:41]=3)[S:34][C:35]([CH:36]=O)=[C:29]2[O:28]1)([CH3:23])([CH3:22])[CH3:21]>C(N(CC)CC)C>[C:20]([SiH2:24][O:25][C:26]([CH3:51])([CH3:52])[CH:27]1[CH2:32][O:31][C:30]2=[C:33]([CH:38]=[CH:39][C:40]3[CH:41]=[CH:42][C:43]([N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])=[CH:44][CH:45]=3)[S:34][C:35]([CH:36]=[CH:12][C:11]3[C:10]([CH3:13])([CH3:14])[O:9][C:8](=[C:15]([C:16]#[N:17])[C:18]#[N:19])[C:7]=3[C:5]#[N:6])=[C:29]2[O:28]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: CCN(CC)c1ccc(C=Cc2sc(C=O)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc(C=Cc2sc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)c3c2OCC(C(C)(C)O[SiH2]C(C)(C)C)O3)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
20 mL of anhydrous chloroform was added to 0.318 g (0.0016 mole) of 2-(3-cyano-4,5,5-trimethyl-5H-furan-2-ylidene)-malononitrile, and 0.640 g (0.00131 mole) of 5. Once in solution, 10 mg of triethylamine were added and the reaction mixture was stirred at room temperature for 12 h. The solvent was removed under reduced pressure. The compound was purified on a silica column with a hexane/ethyl acetate mobile phase.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]#N)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:16].[Ba+2].[OH-:18].S(=O)(=O)(O)O>O>[CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([C:14]([OH:18])=[O:16])([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: N#CC12CC1CN(Cc1ccccc1)C2
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Solvent: O
Product: O=C(O)C12CC1CN(Cc1ccccc1)C2
Yield: 95.7 %

Procedure:
A mixture of 3-benzyl-1-cyano-3-azabicyclo[3.1.0]hexane (2.77 g, 14.0 mmol) and barium hydroxide (4.47 g, 14.2 mmol) in water (100 ml) was heated to reflux for 18 hours. The reaction was then cooled and brought to neutral pH with sulfuric acid. The thick white mixture was filtered and washed twice with ethanol and twice with water. The filtrate was concentrated in vacuo, and the residue mixed with hot ethanol and filtered again. The filtrate was concentrated to provide the title product (2.91 g, 13.4 mmol, 96% yield). 1H NMR (D2O): 7.50 (bs, 5H), 4.36 (s, 2H), 3.9 (bs, 1H), 3.6 (m, 1H), 3.5 (bm, 2H), 2.14 (bs, 1H), 1.53 (bs, 1H), 1.09 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:17]([NH2:19])=[O:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.N1CCCCC1>C(O)C>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:13]=3)[C:3]=2[C:17]([NH2:19])=[O:18])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1
Yield: 97 %

Procedure:
5-amino-3-((4-isopropylphenyl)amino)-1H-pyrazole-4-carboxamide (850 mg) was suspended in 15 mL of ethanol and 4-hydroxybenzaldehyde (601 mg, 1.5 eq.) and piperidine (0.50 eq, 168 μL) was added. Stirred the reaction at reflux until starting material was absent and confirmed by HPLC. After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 5-((4-hydroxybenzylidene)amino)-3-((4-isopropylphenyl)amino)-1H-pyrazole-4-carboxamide as a yellow to orange powder. The product was washed with ethanol to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr (1.15 g, 97% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[O:10][C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:45]=[CH:44][CH:43]=[C:42]3[C:38]=2[CH:39]=[N:40][NH:41]3)O1>>[NH:41]1[C:42]2[C:38](=[C:37]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[O:10][C:9]([C:11]([N:13]5[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]5)=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:45]=[CH:44][CH:43]=2)[CH:39]=[N:40]1
Reactant: CS(=O)(=O)N1CCN(C(=O)c2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl(4-methylsulfonylpiperazin-1-yl)methanone was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to give, after purification by reverse HPLC, 292. MS (Q1) 352 (M+)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:18]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[NH:11][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Yield: 70 %

Procedure:
4-nitro-o-phenylenediamine (15.4 grams, 100 mmol) was dissolved in anhydrous pyridine (70 mL) at 45° C. p-Toluenesulfonyl chloride was added to the reaction mixture in 5 gram portions over the period of 30 minutes. The reaction was then heated to 100° C. for 4 hours. After cooling to room temperature, the mixture was poured into ice/water and this was extracted 3 times with methylene chloride. The combined organic portions were washed with water and brine and dried over anydrous sodium sulfate. Filtration and concentration afforded crude product, which was triturated with hot ethanol to give 32.5 grams of product as yellow powder (70%). M+462.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Br[CH2:15][C:16]([C:18]1[CH:22]=[C:21]([Cl:23])[S:20][C:19]=1[Cl:24])=O>>[Cl:24][C:19]1[S:20][C:21]([Cl:23])=[CH:22][C:18]=1[C:16]1[N:2]=[C:1]([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[S:3][CH:15]=1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Reactant: O=C(CBr)c1cc(Cl)sc1Cl
Product: COC(=O)c1ccc(-c2nc(-c3cc(Cl)sc3Cl)cs2)cc1
Yield: 74 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 3-bromoacetyl-2,5-dichlorothiophene to obtain methyl 4-[4-(2,5-dichloro-3-thienyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 74%. Pale yellow prisms. Melting point: 149 to 150° C.
Reaction SMILES: [OH:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][CH:2]([C:4](=[CH2:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3])(=[O:19])[CH3:18]
Reactant: C=C(C(=O)OCC)C(C)O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C(=O)OCC)C(C)OC(C)=O
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(1-hydroxyethyl)acrylate (40 g) and pyridine (26.9 ml) in dichloromethane (277 ml) was added dropwise acetyl chloride (23.7 ml) at 0° C. The reaction mixture was stirred for 1 hour and quenched with water (200 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate water and an aqueous sodium chloride in turn, and then, dried over magnesium sulfate. After the resultant solution was evaporated, the residue was distilled in vacuo to give ethyl 2-(1-acetoxyethyl)acrylate (41.44 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH:20]([NH:22][CH2:23][CH2:24][CH:25]1[O:30][CH2:29][CH2:28][NH:27][CH2:26]1)=[O:21]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:27]3[CH2:28][CH2:29][O:30][CH:25]([CH2:24][CH2:23][NH:22][CH:20]=[O:21])[CH2:26]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: O=CNCCC1CNCCO1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCNC=O)C3)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-formylaminoethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-6,8-difluoro-7-[2-(2-formylaminoethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([Br:11])[CH:5]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[C:6]([Br:11])[CH:5]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)c(Br)c1
Temperature: 80 °C

Procedure:
The crude 3-bromo-4-fluorobenzoic acid methyl ester is dissolved in 120 mL of N,N-dimethylformamide, 4.32 g (43.1 mmol, 2 eq.) of N-methylpiperazine and 4.46 g (32.3 mmol, 1.5 eq.) of potassium carbonate were added and the reaction mixture heated at 80° C. for 8 hours. The mixture was poured into 300 mL of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[H][H]>O.C(O)C.[Pd](Cl)Cl>[CH3:2][C:3]1[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][C:4]=1[C:5]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:6]
Reactant: [H][H]
Reactant: Cc1c(C(=O)c2ccc(F)cc2)cccc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(N)cccc1C(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 58.7 %

Procedure:
38 ml of hydrochloric acid, 23 g of activated carbon and 12 ml of a solution of 20% palladium chloride in water were added to a solution of 114.7 g of 2-methyl-3-nitro-4'-fluorobenzophenone in 1 liter of ethanol and then a current of hydrogen was passed therethrough for 3 hours. The reaction mixture was filtered and the filter was rinsed with ethanol. The filtrate was concentrated until crystallization began and was iced and then vacuum filtered. The precipitate was empasted with ethanol and dried under reduced pressure to obtain 59.5 g of 2-methyl-3-amino-4'-fluorobenzophenone in the form of white crystals melting at 170°C. Evaporation of the mother liquor and treatment with isopropyl ether gave another 50.5 g of product for a total of 110 g. For analysis, a sample of the product was crystallized from an aqueous solutio of 5% hydrochloric acid and melted at 170°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH3:27])=[C:20]([O:23][CH3:24])[CH:21]=3)[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][C@@H:14]([OH:28])[CH2:15]3)[N:10]=2)=[CH:7][CH:6]=[C:5]([O:29][CH3:30])[N:4]=1.[CH3:31][S:32](O)(=[O:34])=[O:33]>O1CCCC1>[S:32]([O:28][C@@H:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([C:17]3[C:22]([C:9]([C:8]4[C:3]([O:2][CH3:1])=[N:4][C:5]([O:29][CH3:30])=[CH:6][CH:7]=4)=[N:10]2)=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=3)[CH2:15]1)(=[O:34])(=[O:33])[CH3:31]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](O)C[C@H]21
Reactant: CS(=O)(=O)O
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1OC)C(c1ccc(OC)nc1OC)=N[C@@H]1CC[C@@H](OS(C)(=O)=O)C[C@H]21
Temperature: 60 °C
Yield: 98 %

Procedure:
(2R,4aR,10bR)-6-(2,6-Dimethoxy-pyridin-3-yl)-9-ethoxy-8-methoxy-1,2,3,4,4a, 10b-hexahydro-phenanthridin-2-ol (1.5 g; 3.6 mmol) is dissolved in 9 ml of tetrahydrofuran. The solution is heated up to 60° C. 247 μg (3.8 mmol) of methanesulfonic acid are added. After crystallisation the suspension is stirred over night. The crystals are filtered off and dried to obtain 1.73 g (95%) of the title compound (m.p.: 193° C.).
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-])=O)(C)C)(C)(C)C.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[O:12][CH2:11][CH2:10][CH2:9][OH:8]
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)ccc1OCCCO
Temperature: 80 °C
Yield: 87.1 %

Procedure:
To a solution of tert-butyl-[3-(4-chloro-2-nitro-phenoxy)-propoxy]-dimethyl-silane (0.37 g, 1.07 mmol), in a mixture of ethanol (10 mL) and water (3 mL), were added ammonium chloride (0.3 g, 5.37 mmol) and iron powder (0.3 g, 5.6 mmol) and the resulting mixture was heated at 80° C. overnight. The solid was filtered through a CELITE™ pad, the filter cake was washed with ethyl acetate. The filtrate was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified on a silica gel plug to give 0.188 g (87% yield) of 3-(2-amino-4-chloro-phenoxy)-propan-1-ol as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[S:19][C:16]1[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=1
Reactant: Oc1ccc(S)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Temperature: 0 °C
Yield: 46 %

Procedure:
A solution of 2-Chloro-5-nitroaniline (3 g, 17.4 mmole), 4-hydroxythiophenol (2.4 g, 19.0 mmol), cesium carbonate (12.35 g, 38 mmol) in dimethylformamide (35 ml) was heated at 100° C. for 16 hours. Afterwards ice water (200 mL) was added to the solution and to the resultant slurry was added ethyl acetate (200 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a yellow oil. The oil was purified by silica gel chromatography eluting with methylene chloride/methanol (97:3), to provide a yellow solid as the title compound (2.1 g, 46%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CC1C=CC(S([CH2:20][CH2:21][CH2:22][O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)(=O)=O)=CC=1.ClCCl.[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[O:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc(OCCCOC2CCCCO2)cc1

Procedure:
In accordance with literature directions 4-hydroxybenzaldehyde is reacted with the bromo compound 2a in the presence of a phase transfer catalyst (dichloromethane/sodium hydroxide solution/tetra-n-butylammonium hydroxide). After chromatographic purification the aldehyde is obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([NH:31][CH:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:30])=[CH:27][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[O:30])=[CH:39][CH:40]=4)=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3)ncc21
Yield: 62.8 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144), 0.05 g (0.17 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide, 0.04 g (0.22 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75), to give 0.051 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-147).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[O:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13]1.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:19]2[CH:18]=[CH:17][C:16]3[O:12][CH2:13][CH2:14][C:15]=3[CH:20]=2)=[O:8])[CH:10]=1
Reactant: c1ccc2c(c1)CCO2
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)CCO2)c1cc(Br)ccc1Cl
Reaction time: 2 h
Yield: 73 %

Procedure:
5-bromo-2-chloro-benzoyl chloride 2a (10.8 g, 42.5 mmol) was dissolved in 100 mL dichloromethane, followed by addition of 2,3-dihydrobenzofuran 5a (5.11 g, 42.5 mmol) and addition of aluminum trichloride (6.8 g, 51.0 mmol) in batch. The reaction mixture was stirred for 2 hours. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound (5-bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanone 5b (10.47 g, white solid), yield: 72.9%. MS m/z (ESI): 339.0 [M+1]; 1H NMR (400 MHz, CDCl3): δ 7.73 (d, 1H), 7.58 (dd, 1H), 7.53 (dd, 1H), 7.47 (d, 1H), 7.32 (d, 1H), 6.81 (d, 1H), 4.68 (t, 2H), 3.26 (t, 2H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.Cl>COCCOC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:26]([C:21]2[C:20]([C:17]3[CH:16]=[CH:15][C:14]([CH3:13])=[CH:19][CH:18]=3)=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:28])=[O:27])=[N:5][CH:6]=1
Reactant: Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1
Reactant: COc1nc(Br)cnc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccc(C)cc1
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
Sodium hydride (oil free; 0.053 g) was added to a solution of 2-amino-5-bromo-3-methoxypyrazine (0.151 g) in DME (5 ml). The solution was stirred for 10 minutes and then a solution of 4'-methyl-2-biphenylsulphonyl chloride (0.198 g) in DME (2 ml) was added. The solution was allowed to stand for 1 hour and then water (25 ml) was added. 2M Hydrochloric acid (2 ml) was added and the mixture was extracted eith ethyl acetate (2×25 ml). The extracts were washed with water (25 ml) and saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was recrystallised from ethyl acetate to give N-(5-bromo-3-methoxy-2-pyrazinyl)-4'-methyl-2-biphenylsulphonamide (0.12 g) m.p. 204-206° C.; 1H NMR (d6 -DMSO): 2.4 (s,3H), 3.85(s,3H), 7.05-7.2(m,4H), 7.3(dd,1H), 7.55-7.7(m,2H), 7.8(s,1H), 8.1(dd,1H); mass spectrum (+ve FAB, methanol/NBA): 436 (M+H)+.