Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11](I)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[C:11]1[C:2]([Cl:1])=[CH:3][C:4]([O:13][CH3:14])=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=1
Reactant: COC(=O)c1cc(I)c(Cl)cc1OC
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cc(Cl)ccc2Cl)c(Cl)cc1OC
Yield: 84 %

Procedure:
A mixture of Methyl 4-chloro-5-iodo-2-methoxybenzoate (1.8 g, 5.51 mmol), (2,5-dichlorophenyl)boronic acid (2.1 g, 11.03 mmol), Pd(PPh3)4 (403 mg, 0.55 mmol), Na2CO3 (1.75 g, 16.54 mmol) in 1,4-dioxane (50 mL) and water (5 mL) was stirred at reflux under argon for 16 h. The mixture was filtered and filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (1.6 g, 85% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][S:9]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:11])=[O:10])(=O)=O.[CH2:17]([C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)[CH2:18][CH2:19][CH3:20].[I-].[Na+].[C:40](=O)([O-:42])[OH:41].[Na+]>CN(C=O)C.CO>[CH:40]([OH:42])=[O:41].[CH2:17]([C:21]1[CH:22]=[C:23]2[C:28](=[C:29]([O:31][CH:32]3[CH2:33][CH2:34][N:35]([CH2:6][CH2:7][CH2:8][S:9]([CH:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)(=[O:11])=[O:10])[CH2:36][CH2:37]3)[CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)[CH2:18][CH2:19][CH3:20]
Reactant: O=C([O-])O
Reactant: CS(=O)(=O)OCCCS(=O)(=O)C1CCCC1
Reactant: CCCCc1cc(OC2CCNCC2)c2ncccc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCc1cc(OC2CCN(CCCS(=O)(=O)C3CCCC3)CC2)c2ncccc2c1
Product: O=CO
Temperature: 150 °C
Yield: 35 %

Procedure:
A suspension of 3-(cyclopentylsulfonyl)propyl methanesulfonate (for example, as prepared for Intermediate 25) (0.081 g, 0.3 mmol), 6-butyl-8-(4-piperidinyloxy)quinoline (for example, as prepared for Intermediate 4) (0.102 g, 0.360 mmol), sodium iodide (40 mg, 0.3 mmol) and sodium hydrogen carbonate (200 mg, 2.39 mmol) in dry DMF (2 ml) was heated in a Smith Creator™ microwave oven at 150° C. for 15 min. The reaction mixture was applied to an SCX-2 cartridge (20 g), preconditioned with methanol. The cartridge was washed with methanol (4×25 ml) and then eluted with 10% aqueous 0.88 s.g. ammonia in methanol (4×25 ml). The solvents were removed in vacuo and the resultant residue purified by MDAP to afford the title compound (53 mg): LCMS RT=2.81 min; ES+ve m/z 459 (M+H)+
Reaction SMILES: [C@@H:1]1([C:10](O)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7](O)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC>[C@@H:1]1([CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][OH:8]
Reactant: O=C(O)[C@H]1CCCC[C@H]1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OC[C@@H]1CCCC[C@@H]1CO
Temperature: 0 °C
Yield: 100.4 %

Procedure:
63 g of anhydrous cis-1,2-cyclohexanedicarboxylic acid was dissolved in 200 ml of dried ether and the solution was added dropwise to an ice-cooled suspension of 29 g of lithium aluminum hydride in 1000 ml of dried ether. After completion of the dropwise addition, the solution was heated under reflux for 30 minutes, following return to room temperature, 50 ml of water was added thereto, followed by filtration. The filter cake was washed twice with tetrahydrofuran (200 ml each time). The ethereal filtrate and the tetrahydrofuran washings were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resiude was distilled under reduced pressure and fractions boiling at 122° to 125° C. (0.7 mmHg) were collected to obtain 53 g of pure cis-1,2-cyclohexanedimethanol.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[CH2:20][CH3:21])(=[O:3])[CH3:2].[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1[NH:28][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCc1ccc(OS(=O)(=O)O)c2c(C)c(C(C)=O)c(=O)[nH]c12
Product: CCc1cccc2c(NC3CCCC3)c(C(C)=O)c(=O)[nH]c12
Yield: 72.1 %

Procedure:
3-Acetyl-8-ethyl-4-methylsulfoxy-2-quinolinone (2.77g, 0.01 mol) and cyclopentylamine (0.86g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.15g, yield: 72%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([OH:10])=[O:9])[N:6]=1.[C:12]1([CH:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:19][C:20]([C:22]([O:25][NH2:26])([CH3:24])[CH3:23])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:25][C:22]([C:20]([O:19][CH:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:21])([CH3:24])[CH3:23])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: CC(C)(ON)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 5 h
Yield: 92.9 %

Procedure:
135 g of (2-amino-4-thiazolyl)glyoxylic acid are added whilst cooling with ice to a solution of 245 g of O-(1-diphenylmethoxycarbonyl-1-methylethyl)-hydroxylamine in 400 ml of dimethylformamide. The solution is stirred for 5 hours without cooling, and is then added to 4 l of methanol. In order to complete precipitation, stirring continues for 5 hours at 10°, and the product is then filtered off by suction and dried. 320 g (93%) of the title compound are obtained as colourless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[C:4]([C:11]2[C:19]3[C:18]([NH:20][C@H:21]([C:23]4[N:28]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:27](=[O:35])[C:26]5=[C:36]([CH3:39])[CH:37]=[CH:38][N:25]5[N:24]=4)[CH3:22])=[N:17][CH:16]=[N:15][C:14]=3[N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:12]=2)[CH:3]=1.N1C=CC=CC=1.[S:54](Cl)(=[O:57])(=[O:56])[NH2:55]>O1CCCC1>[CH3:39][C:36]1[CH:37]=[CH:38][N:25]2[C:26]=1[C:27](=[O:35])[N:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([C@@H:21]([NH:20][C:18]1[C:19]3[C:11]([C:4]4[CH:3]=[C:2]([NH:1][S:54]([NH2:55])(=[O:57])=[O:56])[CH:10]=[C:9]5[C:5]=4[CH:6]=[CH:7][NH:8]5)=[CH:12][N:13]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:45])([CH3:47])[CH3:46])[C:14]=3[N:15]=[CH:16][N:17]=1)[CH3:22])=[N:24]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(N)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(N)(=O)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.9 %

Procedure:
(S)-2-(1-((5-(6-Amino-1H-indol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (84 mg, 0.13 mmol) was treated with pyridine (15 μL, 0.18 mmol) and sulfamoyl chloride (18 mg, 0.16 mmol) in tetrahydrofuran (1.0 ml) according to the method described in Preparation 175 but stirring at room temperature during 48 h. The residue was purified using SP1® Purification System (0% to 50% hexane-ethyl acetate) to obtain 47 mg (49% yield) of the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:34])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:34][C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:9]=2[C:10]([O:15][CH3:16])=[N:11][CH:12]=1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Br)c2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (72.4 mg) obtained in Step A of Example 92 in DMF (5 mL) was added NBS (38.1 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (67.8 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C([Li])CCC.CCCCCC.CN([CH:31]=[O:32])C>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[CH:10]=[C:9]([CH:31]=[O:32])[S:8][C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: Clc1nc(N2CCOCC2)c2ccsc2n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-chloro-4-morpholinothieno[2,3-d]pyrimidine 38 (1.75 g, 6.85 mmol) in dry THF (40 mL) at −78° C. was added a 2.5M solution of n-butyllithium (nBuLi) in hexane (3.3 mL, 1.2 eq.). After stirring for 1 h, dry DMF (796 μL, 1.5 eq.) was added. The reaction mixture was stirred for 1 h at −78° C. and then warmed slowly to room temperature. After a further 2 h at room temperature the reaction mixture was poured onto ice/water yielding a yellow precipitate which was collected by filtration and air-dried to yield 2-chloro-4-morpholinothieno[2,3-d]pyrimidine-6-carbaldehyde 33 (1.50 g) MS (Q1) 284 (M+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH:5]2[C:6](=[O:10])O[C:8](=[O:9])[CH:4]2[CH2:3]1.[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>>[CH2:1]=[C:2]1[CH2:3][CH:4]2[C:8](=[O:9])[N:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=3)[C:6](=[O:10])[CH:5]2[CH2:11]1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: C=C1CC2C(=O)OC(=O)C2C1
Product: C=C1CC2C(=O)N(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of 5-Methylene-tetrahydro-cyclopenta[c]furan-1,3-dione (2.8 g, 18.4 mmol) and 4-(trifluoromethoxy)benzenamine (2.6 g, 14.7 mmol) was stirred at 180° C. for 0.5 h. The mixture was cooled to room temperature and purified by silica gel column (petroleum/ethyl acetate=5/1) to yield the title compound (3.0 g, 66%). 1H NMR (300 MHz, CDCl3): δ 7.33-7.26 (m, 4H), 4.99 (s, 2H), 3.44-3.41 (m, 2H), 2.84-2.78 (m, 4H); LC-MS: [M+1]+ 312.0.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH2:12][CH2:13][OH:14])=[CH:4][N:3]=1.[CH2:15]([NH2:17])[CH3:16]>CO.C1COCC1>[CH2:15]([NH:17][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]([CH2:12][CH2:13][OH:14])=[CH:4][N:3]=1)[CH3:16]
Reactant: COC(=O)c1cc(CCO)cnc1Br
Reactant: CCN
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1ncc(CCO)cc1C(=O)OC
Temperature: 57.5 °C
Reaction time: 2 h

Procedure:
7.85 g (30.18 mmol) of methyl 2-bromo-5-(2-hydroxyethyl)pyridine-3-carboxylate (free base) were dissolved in 20 ml MeOH and added to a 250 ml 3-neck-round bottom flask with a stirrer bar, a thermocouple, a addition funnel and a cold condenser (capable for −78° C.). The solution was treated with 433 mg (3.018 mmol, 0.1 equiv.) CuBr and heated to 55-60° C. The reaction mixture was treated dropwise with 74 ml (148 mmol, 4.9 equiv.) 2M EtNH2 in THF. The reaction was kept at 55-60° C. for two hour and monitored. If the chromatogram still shows starting material the reaction was treated with additional 20 ml (40 mmol, 1.32 equiv.) 2M EtNH2 in THF and kept another 2 h at 55-60° C.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9].CCN(CC)CC.[CH3:17][C:18]1([CH3:25])[C:22]([CH3:24])([CH3:23])[O:21][BH:20][O:19]1>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.O1CCOCC1>[CH3:8][C:7]1[C:2]([B:20]2[O:21][C:22]([CH3:24])([CH3:23])[C:18]([CH3:25])([CH3:17])[O:19]2)=[C:3]([NH2:9])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(N)c1Br
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cccc(N)c1B1OC(C)(C)C(C)(C)O1
Yield: 40 %

Procedure:
The procedure described in Example 3: step b was followed using 2-bromo-3-methyl-phenylamine (185 mg, 1.0 mmol, Example 25: step a), PdCl2(PPh3)2 (70.2 mg, 0.1 mmol), dioxane (3 mL), and Et3N (729 μL, 6 mmol), 4,4,5,5,-tetramethyl-[1,3,2]-dioxaborolane (453 μL, 3 mmol). Purification by preparative SiO2 TLC (25% EtOAc in hexanes) of the residue yielded the title compound (94 mg, 40%) as a yellow solid. ESI-MS (m/z): Calcd. for C13H20BNO2: 234.1 (M+H) found: 234.1.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH:7]([N:19]([CH3:36])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)C.[OH-].[Li+]>O1CCCC1.CO.O>[CH3:36][N:19]([CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[CH:10]=1)[CH2:6][CH2:5][C:4]([OH:37])=[O:3])[C:20](=[O:35])[C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=1
Reactant: CCOC(=O)CCC(Cc1cn(C)c2ccccc12)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1cn(C)c2ccccc12

Procedure:
A solution of 15 g of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5(1-methyl-indol-3-yl)-pentanoic acid ethyl ester and 1.78 g of lithium hydroxide in 102.5 ml of tetrahydrofuran/methanol/water =2/2/1 is stirred at room temperature for 3 hours and then concentrated by evaporation. The residue is dissolved in 150 ml of water, extracted with ether, acidified to pH=2 with 0.1N hydrochloric acid and extracted three times with ether. The combined organic phases originating from the extraction of the acidic aqueous phase are washed with water and saturated NaCl solution, dried (magnesium sulfate) and concentrated by evaporation. In this way the title compound is obtained in the form of a yellow foam. Rf value=0.10 (ethyl acetate/hexane 1:1).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[C:3]=1[OH:10]
Reactant: C=C[Mg]Cl
Reactant: O=Cc1cccc(Br)c1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
After a solution of 3-bromo-2-hydroxybenzaldehyde (1.35 g, 6.7 mmol) in THF (10 ml) was cooled to 0° C., a solution of vinyl magnesium chloride in THF (2.0M, 8.05 ml, 16.1 mmol) was added thereto under a nitrogen atmosphere over 5 minutes. The mixture was gradually warmed to room temperature and stirred at room temperature for 3 hours. The mixture was cooled to 0° C. and a 20% aqueous ammonium chloride solution (30 ml) was added thereto at 0° C. After the mixture was stirred at room temperature for 30 minutes, it was poured to ice-water (30 ml). The mixture was extracted with ethyl acetate (2×50 ml). The organic layer was combined and successively washed with water (30 ml) and a saturated aqueous NaCl solution (30 ml), followed by drying with anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated to obtain a pale brown oil. This oil was purified by silica gel column chromatography (use of 40 g of Wakogel C-100E, elution with hexane:ethyl acetate=5:1) to obtain 1.24 g of 2-bromo-6-(1-hydroxy-2-propenyl)phenol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10]1.C(O)(=O)C.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:24]1([NH:8][C@H:9]2[C:16](=[O:17])[N:15]3[C@@H:11]([S:12][CH2:13][C@H:14]3[C:18]#[N:19])[CH2:10]2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1CCCC1
Reactant: N#C[C@@H]1CS[C@H]2C[C@@H](N)C(=O)N12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#C[C@@H]1CS[C@H]2C[C@@H](NC3CCCC3)C(=O)N12
Temperature: 45 °C

Procedure:
20 mg of (3R,6R,7aS)-6-amino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carbonitrile trifluoroacetate were dissolved in 1 ml of 1,2-dichloroethane. 2 μl of acetic acid, 6 μl of cyclopentanone and 29 mg of sodium triacetoxyborohydride were successively added. The mixture was heated at 45° C. for 2 h. The solvent was then removed in vacuo. The residue was purified by preparative HPLC (Merck RP18, acetonitrile/water (0.5% trifluoroacetic acid), linear gradient (0–>80% acetonitrile)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[C:7](#[N:10])[CH:8]=[CH2:9]>CO>[C:7]([CH2:8][CH2:9][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:4][CH2:3][C:2]#[N:1])#[N:10]
Reactant: NCCCCN
Reactant: C=CC#N
Solvent: CO
Product: N#CCCNCCCCNCCC#N
Reaction time: 18 h

Procedure:
To a solution of 1,4-diaminobutane 1 (n=4; 25.0 g, 0.28 mol) in methanol (50 mL) was added dropwise a solution of acrylonitrile (31.6 g, 0.60 mmol) in methanol (25 mL) at 0° C. After the addition the mixture was allowed to come to room temperature and then stirred for 18 h. Finally, the solvent was removed in vacuo, to give the diamine 2 as a pale yellow liquid, (57.0 g, quant.).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35].CCN(CC)CC>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (121 mg, 0.28 mmol), isobutyryl chloride (30 mg, 0.29 mmol) and NEt3 (50 μL, 0.36 mmol) in DCM (1 mL) was allowed to stir at r.t. for 2 h then concentrated in vacuo. The resulting residue purified by column chromatography (Si-PCC, MeOH:DCM, 0-6%) followed by triturating with Et2O affording 824 as a white solid (86 mg, 61%). LCMS (method I): RT 3.42 min, [M+H]+ 503.2. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.99 (1 H, m), 7.75-7.74 (1 H, m), 7.30-7.22 (2 H, m), 4.50-4.20 (4 H, brd s), 4.41 (1 H, t, J=8.45 Hz), 4.32-4.21 (1 H, m), 3.98 (1 H, dd, J=8.63, 5.41 Hz), 3.90-3.80 (5 H, m), 3.76 (3 H, s), 3.34 (2 H, q, J=7.49 Hz), 3.28-3.25 (1 H, m), 3.16-3.11 (2 H, m), 2.47-2.46 (1 H, m), 1.44 (3 H, t, J=7.48 Hz), 1.12 (6 H, dd, J=6.82, 2.82 Hz)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C1C=C(Cl)C=C(C(OO)=[O:23])C=1>ClCCl>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[S:5](=[O:23])[CH2:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CCSc2ccc(C=O)cc21
Solvent: ClCCl
Product: CC1(C)CCS(=O)c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,4-Dimethyl-3,4-dihydro-2H-thiochromene-6-carbaldehyde (449 mg, 2.18 mmol, Example 5-28, Step 2) was dissolved in dichloromethane (22.0 mL) and mCPBA (751 mg, 4.35 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was then diluted with dichloromethane, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% MeOH/dichloromethane to afford the desired product as a colorless oil.
Reaction SMILES: [OH-].[Na+].O.C(=O)([O-])O.[Na+].Br[CH2:10][CH2:11]Br.[OH:13][C:14]1[C:19]([CH2:20][CH2:21][OH:22])=[C:18]([CH3:23])[N:17]=[C:16]([SH:24])[N:15]=1>CC(O)C>[OH:22][CH2:21][CH2:20][C:19]1[C:14](=[O:13])[N:15]2[CH2:10][CH2:11][S:24][C:16]2=[N:17][C:18]=1[CH3:23]
Reactant: BrCCBr
Reactant: Cc1nc(S)nc(O)c1CCO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nc2n(c(=O)c1CCO)CCS2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 40 parts of sodium hydroxide in 500 parts of water were added 400 parts of 2-propanol. In this mixture were dissolved 186.23 parts of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol. The resulting solution was added dropwise, during a 2.66 hours period, to a stirred and refluxing mixture of 210 parts of sodium hydrogen carbonate, 1635 parts of 1,2-dibromoethane and 1600 parts of 2-propanol. Upon completion, stirring was continued for 2 hours at reflux temperature. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was stirred three times in 750 parts of trichloromethane at room temperature. The trichloromethane-phases were evaporated and the residue was crystallized from 300 parts of a mixture of trichloromethane and methanol (85:15 by volume) and 100 parts of hexane. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo for 3 hours at 60° C., yielding 51 parts of 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one. The mother-liquor was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was boiled in 50 parts of a mixture of trichloromethane and methanol (85:15 by volume). After the addition of 50 parts of hexane, the whole was stirred to room temperature. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 17 parts of 2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one.