Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH2:9][C:8](=[O:13])[C:7]=2[CH:14]=1.C[O-].[Na+].[C:18](=O)([O:21]C)[O:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][CH2:10][CH:9]([C:18]([O:19][CH3:20])=[O:21])[C:8](=[O:13])[C:7]=2[CH:14]=1
Reactant: COC(=O)OC
Reactant: COc1ccc2c(c1)C(=O)CCCO2
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1CCOc2ccc(OC)cc2C1=O

Procedure:
A mixture of 7-methoxy-3,4-dihydro-1-benzoxepin-5(2H)-one (1.9 g), sodium methoxide (2.8 g) and dimethyl carbonate (40 ml) is heated under reflux for 8 hours with stirring. The reaction mixture is treated in a manner as that in Reference Example 11 to give methyl 7-methoxy-5-oxo2,3,4,5-tetrahydro-1-benzoxepin-4-carboxylate as a colorless oily product (1.7 g). This product (1.6 g) is dissolved in a mixture of methylene chloride (20 ml) and methanol (20 ml). To the solution is added sodium borohydride (0.15 g) in limited amounts. The mixture is stirred. After addition of water, the reaction mixture is extracted with methylene chloride. The organic layers are combined, washed with water, and evaporated to dryness. To the residue are added methanol (5 ml) and 1N aqueous solution of sodium hydroxide (8 ml). The mixture is stirred at 60° C. for 30 minutes. To the reaction mixture are added water and ether, and the mixture is shaken, followed by separating the aqueous layer. The aqueous layer is acidified with dilute hydrochloric acid, and extracted with methylene chloride. The organic layers are combined, washed with water, dried, and concentrated under reduced pressure. To the residue are added dioxane (5 ml) and concentrated hydrochloric acid (1.5 ml), and the mixture is stirred at 100° C. for 30 minutes. After addition of water, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate to afford 7-methoxy2,3-dihydro-1-benzoxepin-4-carboxylic acid as colorless scales (0.41 g), m.p. 176°-177° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[N+:18]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+].[Cl-].CCOC(C)=O>CO.[Zn]>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9]/[CH:8]=[CH:7]/[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([CH:13]=1)[NH2:18]
Reactant: O=[N+]([O-])c1cc(F)ccc1OC/C=C/c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(F)ccc1OC/C=C/c1ccccc1
Temperature: 25 °C

Procedure:
4-Fluoro-2-nitrophenyl (2E)-3-phenylprop-2-enyl ether (5-1, 20.2 g, 73.9 mmol) was dissolved in MeOH (300 mL) and treated with NH4Cl (20.5 g, 370 mmol) and Zn powder (24.2 g, 370 mmol) in small portions to prevent temperature from exceeding 50° C. during the addition. The suspension was vigorously stirred at 25° C. and then at 60° C. until completion as monitored by TLC and LC/MS. Upon completion, EtOAc was added (900 mL) and the reaction was filtered through celite and concentrated. The product was recrystallized from EtOAc/hexanes after a filtration to remove insoluble NH4Cl, and pure 5-fluoro-2-{[(2E)-3-phenylprop-2-enyl]oxy}aniline (5-2) was isolated as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.38 (m, 5H), 6.74 (dd, J=8.8, 4.9 Hz, 1H), 6.72 (d, J=17.4 Hz, 1H), 6.47 (dd, J=9.7, 3.1 Hz, 1H), 6.42 (m, 2H), 4.67 (dd, J=5.9, 1.3 Hz, 2H), 3.22 (br s, 2H); MS (M+H+, C15H14FNO) 244.2 found 244.3 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([CH:7]=1)[O:8][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[C:31]([F:37])[CH:30]=1
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: N#Cc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1F

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and 4-bromomethyl-2-fluoro-benzonitrile (CAS Reg. No. 222978-03-2). Off-white powder (89%). MS (Turbo Spray): m/z=510.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[O:12]2)[N:4]=1.[O-:21]Cl.[Na+].[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:19]2[C:14]([C:13]([OH:12])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:21])[N:4]=1
Reactant: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)nc(C(=O)c2cccnc2C(=O)O)n1
Temperature: 50 °C

Procedure:
490 mg of 5-(4,6-dimethoxy-2-pyrimidinyl)-furo[3,4-b]pyridine-7(5H)-one is dissolved in 50 ml of methanol and the mixture heated with stirring at 50° C. until a homogeneous solution is formed (ca 1/2 hr). 2.6 g of NaOCl is added dropwise and the solution heated for a further 1/2 hr at 55° C. 0.208 g of 50% NaOH is added at 55° and the mixture heated for a further 1/2 hr at this temperature and then cooled in an ice-bath and acidified with 1 ml conc. HCl. The solvent is evaporated and the residue partitioned between 50 ml of CH2Cl2 and 50 ml of water. The organic phase is concentrated to give a white solid, m.p. 71°-73°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][O:19]C(Cl)Cl>C(Cl)Cl.Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH:18]=[O:19])[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCC(=O)N2
Reactant: COC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)NC(=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.29 gm (2.19 mmol) aluminum chloride in 5 ml of methylene chloride was prepared under nitrogen gas N2 and stirred for 15 minutes and then cooled to 0° C. The mixture was treated with 0.2 gm (1.13 mmol) 6-Methoxy-3,4-dihydro-1H-quinolin-2-one in 5 ml of methylene chloride. The reaction mixture was stirred for 10 minutes at this temperature and was then cooled to −5° C. α,α-dichloromethyl methyl ether 0.28 ml (3.07 mmol) was added over a 5 minutes period and the green reaction mixture was slowly warmed to room temperature and stirred for 6 hours. The reaction mixture was diluted with 2N HCl and extracted with methylene chloride (4×10 ml). The combined organics were dried over sodium sulfate, filtered and concentrated to yield an off white solid. The crude product was chromatographically purified on silica gel, eluting with 7/3 ethyl acetate/hexane. There was obtained 125 mg (54%) of an off white solid. MS APCI m/e 206 (p+1)
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: c1cc2c3c(nnc4c3c1OCC4)CCO2
Reactant: O=Cc1ccccc1
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: Cl[P:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Al].Cl.C1(C)C=CC=CC=1>CN(C)C=O>[C:9]1([PH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Al]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise under a nitrogen gas atmosphere to a suspension of 127 mg (4.71 mmol) of aluminum (foil) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at 100° C. for 30 min. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 hydrochloric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, giving 763 mg (4.10 mmol) of diphenylphosphine in 87% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH2:7][CH2:6]2.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH:7]=[CH:6]2
Reactant: COc1ccc2c(c1)CCOC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(=O)occc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 6-methoxyisochroman-1-one (15.1 g), N-bromosuccinimide (NBS; 27 g) and benzoyl peroxide (500 mg) in tetrachloromethane (250 ml) was heated to reflux while irradiating with light for 3 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in triethylamine (100 ml) and stirred at room temperature for 48 hours. The reaction mixture was partitioned between water and ethyl acetate and adjusted to pH 1 with concentrated hydrochloric acid. The organic phase was removed, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel. The product was thus obtained with the molecular weight of 176.17 (C10H8O3); MS (ESI): 177 (M+H+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2CN(C)[CH2:10][N:9](C)[C:8]2=[N:15][N+:16]([O-:18])=[O:17])[CH2:2]1.Cl>C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([NH:9][CH3:10])=[N:15][N+:16]([O-:18])=[O:17])[CH2:2]1
Reactant: CN1CN(C)C(=N[N+](=O)[O-])N(CC2CCOC2)C1
Agent: Cl
Solvent: CCO
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Temperature: 40 °C
Yield: 72.7 %

Procedure:
A mixture comprising 0.7 g of 1-{(tetrahydro-3-furanyl)methyl}-2-(nitroimino)-3,5-dimethylhexahydro-1,3,5-triazine, 5 ml of 1 N hydrochloric acid and 5 ml of ethanol was stirred at 40° C. for an hour. The reaction fluid was concentrated under a reduced pressure and purified by column chromatography to obtain 0.4 g of 1-{(tetrahydro-3-furanyl)methyl}-2-nitro-3-methylguanidine.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[NH4+:13].[OH-]>>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH2:13])=[O:3]
Reactant: [NH4+]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [OH-]
Product: NC(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.7 %

Procedure:
Isatoic anhydride (40 g, 245 mmol) was suspended in 650 mL 1 N NH4OH (2.5 equiv) and stirred at room temperature for 3 days. The precipitate was filtered and washed with water. The product was then dissolved in THF, filtered, and concentrated to dryness. The product was dried by azeotropic distillation with toluene and washed with CH2Cl2 to yield 10.9 g (32.7%) of 2-amino-benzamide.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11].C[O:14][C:15](=O)[CH:16]([CH3:19])[CH2:17]O.[OH-].[Na+]>Cl>[OH:14][CH2:15][CH:16]([C:19]1[NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([OH:2])=[O:12])[C:5]=2[N:11]=1)[CH3:17]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: COC(=O)C(C)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CO)c1nc2c(C(=O)O)cccc2[nH]1
Temperature: 90 °C
Reaction time: 24 h
Yield: 25.8 %

Procedure:
To a solution of 2,3-diaminobenzoic acid methyl ester (2.1 g, 14.1 mmol) in 4 M HCl (90 mL) was added 2-methyl-3-hydroxypropionic acid methyl ester (5 g, 42.3 mmol). The mixture was stirred at ˜90° C. for 24 h. It was neutralized by use of aqueous sodium hydroxide solution to pH-3, and concentrated to dryness. The residue was suspended in methanol, and filtered through a filter paper. After the filtrate was concentrated, the remaining solid residue was dissolved in water and washed with ethyl acetate. The aqueous solution was evaporated in vacuo yielding the title intermediate as a pale yellow oil (˜800 mg). The crude product was used in the next step without further purification. (m/z): [M+H]+ calcd for C11H12N2O3 221.09. found 221.3. 1H-NMR (CD3OD) δ (ppm) 8.1 (d, 1H), 7.9 (m, 1H), 7.6 (t, 1H), 3.8 (m, 2H), 3.6 (m, 1H), 1.4 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:26]([N:33]1[CH2:37][C@H:36]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:35][C@H:34]1[CH:46]=O)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:46][C@@H:34]2[CH2:35][C@@H:36]([O:38][Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40])[CH2:37][N:33]2[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)cc1-c1ccccc1
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of 0.75 g (2.09 mmol) of [2-phenyl-4-aminobenzoyl]methionine methyl ester (compound 8) and 0.7 g (2.1 mmol) of (2S,4R)-1-Boc-4-[t-butyldimethylsilyloxy]-pyrrolidin-2-aldehyde, prepared as in Example 171B, in 10 ml of methanol were added 1 ml of acetic acid, followed by 0.2 g (3.1 mmol) of sodium cyanoborohydride. The reaction mixture was stirred overnight. After removal of the solvent, the residue was partitioned with ethyl acetate and 5% sodium bicarbonate, and extracted 3 times with ethyl acetate. The combined organic solution was washed with water and brine, dried over magnesium sulfate, and solvent was removed. The residue was flash-chromatographed on silica gel (2:1 hexanes-ethyl acetate) to yield 261 mg (74%) of {4-[(2S,4R)-1-Boc-4-(t-butyldimetylsilyl)oxypyrrolidin-2-ylmethyl]amino-2-phenylbenzoyl}methionine methyl ester as a white solid: mp 48° C.; [α]25D−15.6 (c=1.03, CHCl3);
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>>[CH:19]([N:15]1[CH:16]=[CH:17][N:18]=[C:14]1[C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([C:36]4[CH:35]=[N:34][N:33]([CH2:32][CH2:31][O:30][CH:25]5[CH2:26][CH2:27][CH2:28][CH2:29][O:24]5)[CH:37]=4)[CH:23]=[CH:22][C:5]=3[C:6]=2[N:7]=1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: CC(C)n1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)n1ccnc1-c1nc2c(s1)CCOc1cc(-c3cnn(CCOC4CCCCO4)c3)ccc1-2

Procedure:
8-Bromo-2-(1-isopropyl-1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole were reacted under Suzuki conditions to give 2-(1-Isopropyl-1H-imidazol-2-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. LCMS: RT=4.56 min, [M+H]+=506
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13](F)[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].[Cl:17][C:18]1[CH:19]=[C:20]([OH:29])[CH:21]=[N:22][C:23]=1[O:24][CH:25]1[CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:17][C:18]1[CH:19]=[C:20]([O:29][C:13]2[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5])=[C:2]([F:1])[CH:14]=2)[CH:21]=[N:22][C:23]=1[O:24][CH:25]1[CH2:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reactant: Oc1cnc(OC2CCC2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(Oc2cnc(OC3CCC3)c(Cl)c2)cc1F
Temperature: 90 °C
Yield: 11.8 %

Procedure:
2,4,5-trifluoro-N-(methylsulfonyl)benzamide (Preparation 27, 0.317 g, 1.25 mmol), 5-chloro-6-cyclobutoxypyridin-3-ol (Preparation 19, 0.250 g, 1.25 mmol) and potassium carbonate (0.346 g, 2.50 mmol) were suspended in DMSO (16 mL) and heated at 90° C. for 48 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 20% EtOAc (with 0.5% AcOH) in heptane to afford the title compound as a white solid (64 mg, 12%):
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:12][C:11](=[O:13])[C:10]([CH:14]([NH:16]C(=O)C)[CH3:15])=[N:9][N:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[NH2:16][CH:14]([C:10]1[C:11](=[O:13])[NH:12][C:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:8][N:9]=1)[CH3:15]
Reactant: CC(=O)NC(C)c1nnc(Cc2ccc(C)cc2)[nH]c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1

Procedure:
20 g (69.9 mmol) of N-{1-[3-(4-methylbenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]-ethyl}acetamide are stirred under reflux in 200 ml of 2 N hydrochloric acid for 18 h. The cooled mixture is then neutralized using 6 N NaOH and evaporated to dryness in vacuo. The residue is suspended in methanol and the salt is separated off. The concentrated filtrate is flash-chromatographed using dichloromethane/methanol 20/1 and 5/1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.CN1C(=O)CCC1.[CH2:21]([Mg]Cl)[CH:22]([CH3:24])[CH3:23]>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH:5]=1
Reactant: CC(C)C[Mg]Cl
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(CC(C)C)nc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (1.66 g, 8.23 mmol) in dry THF (50 mL), NMP (1.1 mL, 11.5 mmol) is added. The mixture is cooled to −74° C. before a 2 M solution of isobutylmagnesium chloride (7 mL, 14.0 mmol) in THF is added. Stirring is continued at −75° C. for 1 h, before the mixture is warmed to 0° C. The reaction is quenched by carefully adding water. The mixture is diluted with EA, washed with water followed by brine, dried over MgSO4, filtered and concentrated to give crude 2-isobutyl-6-methoxy-isonicotinic acid methyl ester (1.20 g) as an oil; LC-MS: tR=1.37 min; [M+1]+=224.12.
Reaction SMILES: [C@@H:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:10].S(=O)(=O)(O)O.O.[OH-].[Na+].C(#[N:22])C>>[NH2:22][C@@H:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@@H:2]1[OH:10]
Reactant: O[C@@H]1Cc2ccccc2[C@H]1O
Reactant: CC#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H]1c2ccccc2C[C@@H]1O
Temperature: 0 °C
Yield: 63 %

Procedure:
Trans-1,2-indandiol (1.5 g) was dissolved in acetonitrile (25 mL) cooled to 0° C. , and concentrated sulfuric acid (1.1 mL) was added. The mixture was gradually warmed to 20° C. and aged to 3 hours. Water (2 mL) was added and the mixture heated to reflux. Concentrated aqueous sodium hydroxide was added to adjust the pH to 12. The resulting solid was removed by filtration to provide an aqueous acetonitrile solution of cis-1-amino-2-indanol (1.02 g, 63% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH:17]([NH:21][C:31]([NH:30][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:32])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:22][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CC(N)CC4)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CC(NC(=O)Nc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-ylamine (0.095 g, 0.308 mmol) in dichloromethane (5 mL) was added phenyl isocyanate (37 μL, 0.34 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was removed under reduced pressure and the crude product purified using flash column chromatography (SiO2, gradient from 50% EtOAc in hexane to 66% EtOAc in hexane) to give the desired product, 1-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolin-7-yl)-3-phenylurea as a white solid (0.112 g, 84%). Alternative the crude product can be used in the next step without any further purification. M.p. 192-194° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.31 (s, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.36 (m, 2H), 7.20 (m, 4H), 6.86 (m, 3H), 6.32 (d, J=7.6 Hz, 1H), 5.54 (s, 2H), 4.05 (m, 1H), 3.70 (s, 3H), 3.17 (m, 1H), 3.08 (m, 3H), 2.81 (m, 1H), 2.11 (m, 1H), 1.89 (m, 1H); LCMS [M+H]: 428.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[C:19]1[CH:24]=[C:23]([NH2:25])[CH:22]=[C:21]([CH3:26])[N:20]=1>C1COCC1.N1C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:25][C:23]1[CH:22]=[C:21]([CH3:26])[N:20]=[C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)[CH:24]=1)=[O:8])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cc(N)cc(N2CCc3ccccc3C2)n1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)Nc1cc(C)nc(N2CCc3ccccc3C2)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
With ice bath cooling, a solution of ethyl chlorooxoacetate (2.0 g, 14.6 mmol) in THF (25 ml) was dropwise added to a solution of 2-(3,4-dihydro-1H-isoquinolin-2-yl)-6-methyl-pyridin-4-yl-amine (example 4) (2.9 g, 12.1 mmol) in pyridine (40 ml). The mixture was stirred at 75° C. for 1 hr, evaporated and partitioned (AcOEt/NaHCO3-solution). The organic phase was dried (Na2SO4), concentrated and crystallized yielding 3.1 g (75%) of the title compound as light brown solid. Mp. 128-129° C. (AcOEt), MS: m/e=340 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:16])[C:10]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)=[O:5])C.[Li+].[OH-]>CO.O>[CH3:16][N:9]1[C:10]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1-n1cccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1-n1cccc1

Procedure:
To a solution of 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid ethyl ester (20 g, 91.2 mmol; available from Butt Park Ltd., Camelford, Cornwall, UK) in methanol (100 mL) and water (100 mL) was added LiOH (2.4 g, 100 mmol). The reaction mixture was stirred at reflux for 4 hours and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water, acidified to pH 2 with concentrated HCl (9 mL), and extracted with ethyl acetate. The combined extracts were evaporated in vacuo to give 1-methyl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid which was used without further purification.