Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].[NH2:26][C@H:27]1[C@H:33]([OH:34])[CH2:32][CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]1>ClCCl.CN(C)C1C=CN=CC=1.CCCCCCC>[C:12]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:26][C@H:27]2[C@H:33]([OH:34])[CH2:32][CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]2)=[O:23])=[CH:24][CH:25]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H](N)C1
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Reaction time: 2 h

Procedure:
12.91 g of p-toluenesulphonyl chloride dissolved in 15 ml of dichloromethane were added at room temperature in the course of 15 minutes to 1.94 g of 4-(tert-butoxy)-benzoic acid and 2.63 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture was stirred for 2 hours and added in the course of 1 hour to 2.30 g of tert-butyl (3R,4R)-3-amino-4-hydroxy-azepan-1-carboxylate dissolved in 10 ml of dichloromethane. After stirring for 1 hour the reaction mixture was washed with 20 ml of 1N NaOH, 20 ml of 1N HCl and 20 ml of water. All aqueous phases were washed in succession with 10 ml of dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and the solvent was evaporated. The foam-like residue obtained was dissolved in 80 ml of hot heptane and crystallized at room temperature overnight. The crystals were washed with 10 ml of heptane and dried to yield 3.23 g of tert-butyl (3R,4R)-3-(4-tert-butoxy-benzoylamino)-4-hydroxy-azepan-1-carboxylate, m.p. 134-135° C.
Reaction SMILES: [Na].[C:2](=[N:15]O)([C:4]12[CH2:13][CH:9]([CH2:10][CH2:11][CH2:12]1)[CH:8]1[CH2:14][CH:5]2[CH2:6][CH2:7]1)[CH3:3].Cl>C(O)C.O>[NH2:15][CH:2]([C:4]12[CH2:13][CH:9]([CH2:10][CH2:11][CH2:12]1)[CH:8]1[CH2:14][CH:5]2[CH2:6][CH2:7]1)[CH3:3]
Reactant: CC(=NO)C12CCCC(C1)C1CCC2C1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(N)C12CCCC(C1)C1CCC2C1
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
1.93 g (83.9 mmoles) of metallic sodium powder were added in small portions into a solution of 1.00 g (4.83 mmoles) of 1-acetyltricyclo[4,3,1,12,5 ]undecane oxime in anhydrous ethanol (16 ml) kept under reflux with stirring over a period of 15 minutes. Then, the reaction mixture was heated under reflux for an additional 15 minutes and the mixture was allowed to cool. The reaction mixture was diluted with water (5 ml), then neutralized with 5% hydrochloric acid and then concentrated. The residue was made alkaline with 5% aqueous sodium hydroxide solution and then extracted with diethyl ether. The ether solution was dried and concentrated to afford 0.58 g (yield 62%) of 1-(1-aminoethyl)-tricyclo[4,3,1,12,5 ]undecane.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:12]([CH3:22])[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:22][C:12]1[C:13]([CH:14]([CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:18])=[O:16])=[C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCCCC1
Yield: 51.2 %

Procedure:
Piperidine (0.198 mL; 2.00 mmol) was added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL) and the reaction mixture was irradiated in a microwave oven at 100° C. for 30 min. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.094 g (51%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([OH:38])=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:45][C:46]1[CH:47]=[N:48][C:49](Cl)=[N:50][CH:51]=1.Cl>CN(C)C=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([O:38][C:49]4[N:50]=[CH:51][C:46]([Br:45])=[CH:47][N:48]=4)=[CH:34][N:33]=3)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(O)cn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ncc(Oc3ncc(Br)cn3)cn2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 4-tert-butyl-N-{6-[2-(5-hydroxypyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (200 mg) in dimethylformamide (4 ml) is added potassium carbonate (154 mg), 5-bromo-2-chloropyrimidine (216 mg), and the mixture is stirred at 50° C. for two hours. The reaction mixture is acidified with cold hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with water and brine, and dried over anhydrous sodium sulfate, and evaporated to remove the solvent. The oily residue is purified by silica gel column chromatography (solvent; chloroform/ethyl acetate=50:1), and the fractions are evaporated to remove the solvent. The resulting crude crystals are recrystallized from methylene chloride/isopropyl ether to give 4-tert-butyl-N-{6-[2-(5-(5-bromopyrimidin-2-yloxy)pyrimidin-2-yloxy)ethoxy]-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (238 mg) as colorless needles.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:18]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[N:7]=1.Cl.Cl.[NH2:26][CH2:27][CH2:28][NH:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.C(OCC)(=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][CH2:28][CH2:27][NH:26][C:2]2[C:3]3[N:4]([N:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:18]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=3[Cl:15])[N:7]=2)=[N:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CCOC(=O)c1cc2c(Cl)nc(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)cn2n1
Temperature: 150 °C

Procedure:
1 g (5 mmol) of ethyl 4-chloro-6-(2,4-dichlorophenyl)pyrazolo[1,5-a]pyrazine-2-carboxylate (Example 12A) was initially charged in 15 ml of dry DMSO, and 1.55 g (4.22 mmol) of 6-[(2-aminoethyl)amino]nicotinonitrile dihydrochloride (Example 2A) and 5.8 ml (33.5 mmol) of N,N-diisopropylethylamine were added and the mixture was heated in a microwave at 150° C. for 30 min. Ethyl acetate and 10% strength citric acid were added, and the reaction mixture was extracted. The organic phase was washed with sodium chloride solution and dried over magnesium sulfate. This gave, after concentration, 1.4 g (70% of theory) of the product as a solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:17])[CH:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15]>CN(C=O)C.[Cl-].[Na+].O>[CH3:5][O:6][C:7](=[O:17])[CH:8]([N:1]=[N+:2]=[N-:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[I:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C(Br)c1ccccc1I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(N=[N+]=[N-])c1ccccc1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of NaN3 (10.6 g, 163 mmol) in DMF (100 mL) is added bromo-(2-iodophenyl)-acetic acid methyl ester (19.3 g, 54.4 mmol) and the mixture is stirred at RT for 18 h. Brine is added and the mixture is extracted with ether (10×100 mL). The combined organic layers are washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound which is used directly in the next step.
Reaction SMILES: [N:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[I:19])=[N+:2]=[N-:3].O(CC)CC.[ClH:25]>>[ClH:25].[N:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH2:9])=[CH:6][C:5]=1[I:19])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N=[N+]=[N-])c(I)c1
Agent: Cl
Solvent: CCOCC
Product: [N-]=[N+]=Nc1ccc(CN)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
tert-Butyl 4-azido-3-iodobenzylcarbamate (936.0 mg, 2.5 mmol) was dissolved in Et2O.HCl (2.0 N in Et2O) (10 ml) was added to the solution. The mixture was stirred at r.t. overnight. The solvent was removed under vacuum and the residue washed with a mixture of CH2Cl2 and MeOH (8:2) affording 350 mg (45%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:13](Br)[C:14]#[CH:15]>C(O)(C)C>[CH2:15]([O:7][C:6]([C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)=[O:8])[C:14]#[CH:13]
Reactant: C#CCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#CCOC(=O)c1ccc(O)cc1
Yield: 62.9 %

Procedure:
p-Hydroxybenzoic acid (0.724 mole) and sodium hydroxide (0.724 mole) were dissolved in 50% isopropyl alcohol (400 ml). Propargyl bromide (0.724 mole) was added and the solution was heated to reflux for 6 hours. The solution was then cooled and the isopropyl alcohol was removed under vacuum. The residue was taken up in methylene chloride (200 ml), washed with water (200 ml), aturated sodium bicarbonate, saline and dried over magnesium sulfate. Removal of the solvent yielded crude product, which was recrystallized, from CCI4 to give pure propargylparaben. (62.9% yield) m.p. 107-108° C.
Reaction SMILES: ClC1C(Cl)=CC=CC=1N1CCCN([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]3)=[CH:23][CH:22]=2)CC1.[Na+].[I-].[N:34]1([C:40]2[C:45]3[O:46][CH2:47][C:48](=[O:50])[NH:49][C:44]=3[CH:43]=[CH:42][CH:41]=2)[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:31]=[C:27]1[CH2:26][CH2:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:37]3[CH2:38][CH2:39][N:34]([C:40]4[C:45]5[O:46][CH2:47][C:48](=[O:50])[NH:49][C:44]=5[CH:43]=[CH:42][CH:41]=4)[CH2:35][CH2:36]3)=[CH:22][CH:23]=2)[NH:28]1
Reactant: O=C1COc2c(cccc2N2CCNCC2)N1
Reactant: O=c1ccc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5c4OCC(=O)N5)CC3)cc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
A mixture of intermediate 4 (110 mg, 0.37 mmol) and NaI (110 mg, 0.74 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 59 (118 mg, 0.5 mmol) and anhydrous K2CO3 (138 mg, 1.92 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 8-(4-(4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl)piperazin-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (compound 38) (55 mg, 34%). 1H NMR (300 MHz, CDCl3): δ 10.56 (s, 1H), 9.96 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.85 (t, 1H), 6.57-6.43 (m, 4H), 4.53 (s, 2H), 3.92 (t, J=5.7 Hz, 2H), 2.97 (br, 4H), 2.78 (t, J=6.9 Hz, 2H), 2.43-2.38 (m, 4H), 1.72-1.58 (m, 4H). HPLC: 99%, RT 1.970 min. MS (ESI) m/z 451.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:29][CH:30]([C:32]([OH:34])=[O:33])[CH2:31]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)C1CNC1
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.4 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde (D52) (100 mg), methyl 3-azetidinecarboxylate (57.4 mg) and acetic acid (1.428 μL) in dichloromethane (DCM) (8 mL) and N,N-dimethylformamide (DMF) (0.400 mL) stirred under nitrogen at room temperature for 20 min was added sodium triacetoxyborohydride (106 mg). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated, separated between water and EA, the water phase was extracted by EA. The organic phases were concentrated in vacuo. The residue was dissolved in Isopropanol (8.00 mL) and water (0.800 mL), 20% sodium hydroxide (0.5 mL) was added, then the reaction mixture stirred at room temperature for overnight. The mixture was neutralized with acetic acid, the resulting solution was concentrated and the residue was purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-3-azetidinecarboxylic acid (E23) (32 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.12 (3H, t), 1.35 (6H, d), 2.92 (4H, m), 3.44 (2H, m), 3.63 (1H, m), 4.29 (4H, m), 4.86 (1H, m), 7.38 (3H, m), 7.74 (1H, d), 8.02 (1H, dd), 8.14 (1H, d), 10.18 (1H, br s), 13.18 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C25H28ClN3O3S requires 485. found 486.2 (M+H+).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)[NH2:2].[CH2:19]([N:22]=[C:23]=[O:24])[CH:20]=[CH2:21]>C1COCC1>[CH2:19]([NH:22][C:23]([NH:2][NH:1][C:3]1[N:4]=[C:5]([C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:13])[C:6]2[S:11][CH:10]=[CH:9][C:7]=2[N:8]=1)=[O:24])[CH:20]=[CH2:21]
Reactant: C=CCN=C=O
Reactant: NNc1nc(C(=O)c2cccs2)c2sccc2n1
Solvent: C1CCOC1
Product: C=CCNC(=O)NNc1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A mixture of 2-hydrazinothieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (100 mg, 0.36 mmol) and THF (5 mL) was treated with allyl isocyanate (32 μl, 0.36 mmol), stirred at room temperature for 1 h and filtered to give the title compound (88 mg, 68%) as a yellow solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[F:11][C:12]([F:28])([F:27])[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:14]=1[C:15](OC)=[O:16].[K].[Na]>C1(C)C=CC=CC=1>[F:11][C:12]([F:27])([F:28])[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[C:14]=1[CH2:15][OH:16]
Reactant: COC(=O)c1c(C(F)(F)F)cccc1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K]
Solvent: Cc1ccccc1
Product: OCc1c(C(F)(F)F)cccc1C(F)(F)F
Reaction time: 4 h
Yield: 94.1 %

Procedure:
58 ml of a 1.2M solution of diisobutylaluminium hydride (DIBAH) were added at 0° C. to a solution of 5.59 g of the product of Stage A and 60 ml of toluene. The temperature was allowed to return to 20° C. and the reaction mixture was stirred for 4 hours, then poured into a molar solution of potassium and sodium double tartrate and extracted with isopropyl ether. The aqueous phase was saturated with sodium chloride, followed by extraction with ethyl acetate, drying, filtering, rinsing and bringing to dryness to obtain after chromatography on silica (eluant: hexane-ethyl acetate (9-1)), 4.72 g of the desired product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][NH:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21].Br[CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]1>CC(C)=O>[CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH2:17][CH2:18][NH:19][C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])[CH:27]=1
Reactant: BrC1C=CCCC1
Reactant: O=C(NCCc1c[nH]c2ccc(O)cc12)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(OC3C=CCCC3)cc12)C1CC1

Procedure:
1.98×10-2 mol of potassium carbonate, 1.33×10-2 mol of N-[2-(5-hydroxyindol-3-yl)ethyl]cyclopropylcarboxamide dissolved in 20 cm3 of anhydrous acetone, and 2.1×10-2 mol of 3-bromocyclohexene are introduced into a 50 cm3 flask with a ground neck. The mixture is heated under reflux for 22 hours. The reaction medium is filtered and the filtrate is evaporated under reduced pressure. Recrystallisation of the evaporation residue in ethyl acetate yields purified N-{2-[5-(cyclohexen-3-yloxy)indol-3yl]ethyl}-cyclopropylcarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([OH:23])[CH2:12]2)=[O:10])=[C:4]([C:24](=[O:31])[NH:25][CH:26]([CH:28]2[CH2:30][CH2:29]2)[CH3:27])[CH:3]=1.[H-].[Na+].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1.Cl>CN(C)C=O>[CH3:44][C:34]1[CH:39]=[CH:38][C:37]([S:40]([O:23][C:13]2[CH2:12][CH:11]([C:9](=[O:10])[NH:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[C:24](=[O:31])[NH:25][CH:26]([CH:28]3[CH2:29][CH2:30]3)[CH3:27])[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(O)=NN1c1ncccc1Cl)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OC2=NN(c3ncccc3Cl)C(C(=O)Nc3ccc(Cl)cc3C(=O)NC(C)C3CC3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A mixed liquid comprising 2.0 g of N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-3-hydroxy-4,5-dihydro-1H-pyrazole-5-carboxamide and 41 ml of N,N-dimethylformamide was cooled to 0° C., and 0.2 g of sodium hydride (60% oil suspension) was added. After stirring for one hour, 1.2 g of p-toluenesulfonyl chloride was added at 0° C. After stirring for 1.5 hours, the reaction liquid was poured to 120 ml of a 1 M HCl aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 2.45 g of the desired product in the form of a paste.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[C:39]1([C:45]2[CH:50]=[CH:49][C:48]([C:51](Cl)=[O:52])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([C:45]2[CH:50]=[CH:49][C:48]([C:51]([C:35]3[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=3)[C@@H:8]3[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]3[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])=[O:52])=[CH:47][CH:46]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(-c4ccccc4)cc3)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-((4-Phenyl)phenylcarbonyl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using (4-phenyl)phenylcarbonyl chloride instead of benzophenone) as a colourless foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([OH:18])[CH2:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][NH:11][CH2:12]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C@H:27]([CH3:31])[C:28](O)=[O:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([OH:18])[CH2:16][C@H:15]([CH3:17])[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][N:11]([C:28](=[O:29])[C@H:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19])[CH3:31])[CH2:12]2
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: C[C@@H]1C[C@H]2CNC[C@H]2[C@](O)(c2ccccc2F)C1
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](C)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Yield: 48.5 %

Procedure:
By working as in Example 33, but starting with 2.5 g of (3aS,4S,6R,7aR)-4-(2-fluorophenyl)-6-methyl-4-perhydroisoindolol and 2.17 g of 2-(S)-(2-methoxyphenyl)propionic acid, and after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 4 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume), 3.87 g of a solid are obtained, which solid is recrystallized in acetonitrile to give 2 g of (3aS,4S,6R,7aR)-4-(2-fluorophenyl)-2-[2-(S)-(2-methoxyphenyl) propionyl]-6- methyl-4-perhydroisoindolol, in the form of a white solid melting at 170° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[C:26](=[O:31])[CH2:27]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Reactant: CN1CCNCC1=O
Agent: Cl
Product: CN1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)CC1=O

Procedure:
The title compound was prepared in analogy to Example 38 using 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Intermediate J, 50 mg, 0.160 mmol) and 1-methylpiperazin-2-one hydrochloride (36.5 mg, 0.320 mmol) (tR 3.11 min (conditions 5), MH+=391, 1H-NMR in DMSO-d6: 8.84 (d, 1H); 8.33 (d, 1H); 7.95 (s, 1H); 7.85 (d, 1H); 7.71 (d, 1H); 7.48 (m, 1H); 7.46 (s, 1H); 7.15 (d, 1H); 4.42 (s, 2H); 4.06 (s, 2H); 3.75 (m, 2H); 3.49 (m, 2H); 2.83 (m, 3H)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][S:16][CH3:17])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][S:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCSC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCSC
Yield: 71 %

Procedure:
A mixture of 6-methoxy-7-(2-methylthioethoxy)-3,4-dihydroquinazolin-4-one (1.07 g, 4.0 mmol), thionyl chloride (20 ml) and DMF (4 drops) was heated at reflux for 2 hours and then allowed to cool. The excess thionyl chloride was removed by evaporation and the residue was azeotroped with toluene. The solid residue was partitioned between aqueous sodium hydrogen carbonate and methylene chloride, the organic phase was separated and washed with brine. The organic phase was passed through phase separating paper, and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-methylthioethoxy)quinazoline (810 mg, 71%).