Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[CH:7]=1.[CH3:22][C:23]([O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])([CH3:26])[C:24]#[CH:25].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>N1C=CC=CC=1>[C:14]([NH:13][C:11]1[S:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([O:27][C:23]([CH3:22])([CH3:26])[C:24]#[CH:25])[CH:29]=4)[CH:21]=[CH:20][CH:19]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)cc2s1
Reactant: C#CC(C)(C)Oc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: C#CC(C)(C)Oc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(C)=O)sc4c3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-1,3-benzothiazol-2-yl]acetamide (160 mg, 0.534 mmol) produced in Example A40(x), 3-[(1,1-dimethylprop-2-yn-1-yl)oxy]benzoic acid (215 mg, 1.07 mmol) in pyridine (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (407 mg, 1.07 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL). The organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100), and crystallized from ethyl acetate to give the title compound (181 mg, 70%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[N:3]=1
Reactant: CC(C)(C)N
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Product: CC(C)(C)Nc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Yield: 65 %

Procedure:
(±)-cis-4-(2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol from Example 4 (0.544 g, 2.0 mmol) and tert-butylamine (15 mL) were heated at 80° C. in a Parr bomb for 28 hours. The resulting solution was concentrated and the residual oil was dried by evaporation of ethanol and chromatographed on silica gel. Title compound was eluted with 5% methanol-chloroform; crystallization from acetonitrile gave white powder (0.392 g, 65%), m.p. 161-163° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:41][CH2:42][CH3:43])[C:34]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)[C:29]([OH:31])=O)[CH3:24].Cl.[NH:45]1[C:49]([C:50]2[CH:51]=[C:52]3[C:62](=[CH:63][CH:64]=2)[O:61][C:55]2([CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)[CH2:54][C:53]3=[O:65])=[N:48][N:47]=[N:46]1>O.CN(C=O)C.CCN(CC)CC>[CH2:42]([O:41][C:33]1[CH:32]=[C:28]([C:29]([N:58]2[CH2:59][CH2:60][C:55]3([CH2:54][C:53](=[O:65])[C:52]4[C:62](=[CH:63][CH:64]=[C:50]([C:49]5[NH:48][N:47]=[N:46][N:45]=5)[CH:51]=4)[O:61]3)[CH2:56][CH2:57]2)=[O:31])[CH:27]=[C:26]([O:25][CH2:23][CH3:24])[C:34]=1[C:35]1[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=1)[CH3:43]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Et3N (38 μL), HOBT (41 mg) and WSC hydrochloride (52 mg) were added to a DMF (3 ml) solution of 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (65 mg), 6-(tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (87 mg), and stirred overnight at room temperature. Water was added to the reaction liquid, the formed solid was taken out through filtration, then fully washed with water and ether. The solid was dried under reduced pressure to obtain the title compound. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d, J=4.0 Hz), 8.23 (11, dd, J=8.0, 4.0 Hz), 8.04 (1H, s), 7.92 (1H, s), 7.32 (1H, d, J=8.0 Hz), 6.68 (2H, s), 4.32-4.18 (1H, m), 4.08 (4H, q, J=8.0 Hz), 3.86 (3H, s), 3.64-3.20 (3H, m), 2.97 (2H, s), 2.10-1.75 (4H, m), 1.37 (6H, t, J=8.0 Hz). MS [M+H]+=558.
Reaction SMILES: C(F)(F)=C(Cl)[F:3].[NH:7]1[CH:14]=[CH:13][C:11](=[O:12])[NH:10][C:8]1=[O:9].FF>F>[F:3][C:13]1[C:11](=[O:12])[NH:10][C:8](=[O:9])[NH:7][CH:14]=1
Reactant: FC(F)=C(F)Cl
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: F
Agent: FF
Product: O=c1[nH]cc(F)c(=O)[nH]1
Reaction time: 0.17 h

Procedure:
In a 200 ml volume flask made from "Daiflon Resin" (trifluorochloroethylene resin manufactured by Daikin Kogyo Co., Ltd.) which is equipped with a stirrer, a cooler, an inlet for gas and a thermometer, a designed amount of uracil and an aqueous solution of hydrofluoric acid (50 g) are charged, and the contents are stirred at a temperature lower than the reaction temperature to dissolve uracil in the aqueous solution of hydrofluoric acid. A designed amount of fluorine gas diluted or not with nitrogen gas is introduced therein over a period of 30 minutes to 1 hour. Then, nitrogen gas is made to pass through the flask for about 10 minutes to remove fluorine present in the reaction system. The reaction solvent is distilled off with heating to obtain crude 5-fluorouracil.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C@H:5]1[C@H:14]2[CH2:15][CH2:16][N:17]([C:18]([C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH2:26])=[O:19])[C@H:13]2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]1.C(N(CC)CC)C.[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1.CCOC(OC(OCC)=O)=O>O1CCCC1.O>[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:26][C@@H:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[C:18]([N:17]2[C@@H:13]3[C@@H:14]([C@H:5]([CH2:4][O:3][CH3:2])[NH:6][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=43)[CH2:15][CH2:16]2)=[O:19])=[O:44])=[CH:46][CH:47]=1
Reactant: O=C(O)c1ccc(-c2ncc[nH]2)cc1
Reactant: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Agent: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc(-c2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine hydrochloride (200 mg, 0.480 mmol) in tetrahydrofuran (5 ml) were added triethylamine (0.199 ml, 1.44 mmol), 4-(1H-imidazol-2-yl)benzoic acid (99.0 mg, 0.529 mmol) and DEPC (0.079 ml, 0.529 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The obtained residue was subjected to column chromatography using silica gel and eluted with ethyl acetate-methanol (1:0-4:1) to give the title compound (150 mg, 61%) as an amorphous form.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[C:9]([Si](C)(C)C)[S:10][CH:11]=1.[CH3:16][C:17]1[N:18]=[CH:19][S:20][C:21]=1[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.CCCCC.O>[CH3:6][C:7]1[N:8]=[CH:9][S:10][C:11]=1[CH:22]([C:21]1[S:20][CH:19]=[N:18][C:17]=1[CH3:16])[OH:23]
Reactant: Cc1csc([Si](C)(C)C)n1
Reactant: Cc1ncsc1C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Cc1ncsc1C(O)c1scnc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 12.8 ml) was added dropwise to a stirred solution of 4-methyl-2-trimethylsilylthiazole (5 g) in anhydrous tetrahydrofuran/diethyl ether/pentane (4:4:1, 75 ml) at -100° C. under an atmosphere of dry nitrogen. After 90 minutes, 4-methyl-5-thiazolecarbaldehyde (J. Amer. Chem. Soc., 1982, 104, 4934-4943) (4 g) was added. After a further 3 hours at -100° C., water was added and the mixture was warmed to room temperature. Saturated aqueous ammonium chloride solution was added and the organic phase was separated, dried and evaporated. The residue was crystallised from ethyl acetate to give bis(4-methyl-5-thiazolyl)methanol. This material in dichloromethane was oxidised using manganese dioxide to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH2:34]O)=[N:26][C:27]=2[O:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:56].[Cl-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH2:34][Cl:56])=[N:26][C:27]=2[O:32][CH3:33]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)cc1OCc1c(OC)ccc(F)c1F
Reactant: ClC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CCl)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-hydroxymethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.34 g) and triphenyl-phosphine (0.43 g) in N,N-dimethylformamide (4 mL) was added carbon tetrachloride (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 10% aqueous sodium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/20) to give 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-chloromethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.34 g). The mixture of the obtained 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-chloromethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (50 mg), dimethylamine (50% aqueous solution, 0.1 mL) and sodium iodide (14 mg) in 2-propanol (1 mL)-acetonitrile (1 mL) was stirred at 60° C. for 4 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=7/3). The obtained product was suspended in diethyl ether, and collected by filtration. The collected material was dried under reduced pressure to give the title compound (12 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O>[N:17]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2)=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOc1ccc2[nH]c(=O)ccc2c1
Temperature: 80 °C
Yield: 97.3 %

Procedure:
A suspension of 6-(3-chloropropoxy)carbostyril (100 g) and sodium azide (33 g) in dimethylformamide is refluxed at 80° C. for 4 hours. After the mixture is allowed to cool, to the mixture is added ice-water, and the precipitated crystals are collected by filtration, washed with diethyl ether, and dried to give 6-(3-azidopropoxy)carbostyril (100 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])[CH3:12]>>[CH2:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([NH:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)(=[O:21])=[O:20])[CH3:12]
Reactant: CCc1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc2nonc2c1
Product: CCc1ccccc1S(=O)(=O)Nc1ccc2nonc2c1

Procedure:
Analogously to Example 1, by reaction of 5-amino-2,1,3-benzoxadiazole (obtainable by reduction of 5-nitro-2,1,3-benzoxadiazole-1- or 3-N-oxide with triethyl phosphite) with 2-ethylbenzenesulfonyl chloride, 2-ethyl-N-(2,1,3-benzoxadiazol-5-yl)-1-benzenesulfonamide is obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].F[C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:18])=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1>CC(N(C)C)=O>[OH:5][CH2:4][CH2:3][O:6][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:18])=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: Oc1ncnc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: OCCOc1ccc2c(O)ncnc2c1
Temperature: 60 °C
Yield: 45.1 %

Procedure:
A mixture of sodium hydride (60% in oil, 7.67 g, 189.6 mmol) and dimethylacetamide (160 ml) were cooled in an ice-bath under a nitrogen atmosphere and then ethylene glycol (18.2 g, 284 mmol) was slowly added. The reaction mixture was warmed to 60° C. for 10 minutes and then 7-fluoroquinazolin-4-ol (7.75 g, 47.3 mmol) was slowly added. The reaction mixture was heated to 110° C. for 16 hours and then the mixture was concentrated to approximately half volume. The mixture was poured into water and the pH of the solution was adjusted to 5 with dilute hydrochloric acid. The resultant precipitate was filtered and then dried in a vacuum oven at 65° C. for 16 hours. The residue was triturated with diethyl ether to give 7-(2-hydroxyethoxy)quinazolin-4-ol (4.4 g) as an off white solid which was used in subsequent steps without further purification: MS (+ve ESI): 207 (M+H)+ MS (−ve ESI): 205 (M−H)−.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:25]=[CH:24][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[C:8]([F:26])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][C:9]3[CH:24]=[CH:25][C:6]([Cl:5])=[CH:7][C:8]=3[F:26])=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: BrCCBr
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
1,2-Dibromoethane (5.4 ml, 62 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (5 g, 15.6 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (8.6 g, 62 mmol) in DMF (50 ml) and the mixture stirred for 18 hours at ambient temperature. Water was added and the resulting precipitate was collected by filtration. The solid was purified by chromatography on neutral alumina eluting with methylene chloride/methanol (95/5). The semi-purified product was repurified by chromatography on silica eluting with methylene chloride/methanol (97/3). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 7-(2-bromoethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (3.58 g, 54%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:26][CH2:25][C:22]3([CH2:24][CH2:23]3)[C@H:21]([OH:27])[CH2:20]2)[CH2:10][C@H:9]1[CH3:28])=O)(C)(C)C.[ClH:29]>ClCCl.O1CCOCC1>[ClH:29].[ClH:29].[OH:27][C@@H:21]1[CH2:20][N:19]([CH2:18][CH2:17][CH2:16][N:11]2[C:12](=[O:15])[CH2:13][CH2:14][NH:8][C@H:9]([CH3:28])[CH2:10]2)[CH2:26][CH2:25][C:22]21[CH2:23][CH2:24]2
Reactant: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CN(CCCN2CCC3(CC3)[C@H](O)C2)C(=O)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.500 g (1.26 mmol) of (R)-4-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (example ID) in 8 ml of dichloromethane was treated at 0° C. with 3.16 ml (12.64 mmol, 10 eq.) of 4 M hydrogen chloride solution in dioxane. The solution was stirred overnight and warmed up to room temperature. The solution was evaporated, suspended in toluene and evaporated (3 times) to give 0.610 g (quantitative, purity: 76%) of the title compound as white solid. MS: 296.3 (MH+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[C:16]2[C:15]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=O)OC(C)(C)C)[CH2:20][CH2:19]3)=[N:14][CH:13]=[N:12][C:11]=2[S:10][C:9]=1[CH3:32]>C1COCC1>[CH3:7][C:8]1[C:16]2[C:15]([NH:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([NH:24][CH3:25])[CH2:20][CH2:19]3)=[N:14][CH:13]=[N:12][C:11]=2[S:10][C:9]=1[CH3:32]
Reactant: Cc1sc2ncnc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H]1CC[C@H](Nc2ncnc3sc(C)c(C)c23)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of LiAlH4 (160 mg, 2.1 mmol, 5.0 eq) in THF (5 mL) was added a solution of tert-butyl trans-4-(5,6-dimethylthieno[2,3-d]pyrimidin-4-ylamino)cyclohexylcarbamate (160 mg, 0.42 mmol, 1.0 eq) in THF (5 mL). The mixture was stirred at 80° C. for 2 hours. The reaction was quenched with a mixture of THF/H2O and filtered. The cake was washed with CH2Cl2. The filtrate was concentrated and the residue was purified by column chromatography (CH2Cl2/MeOH/Et3N=20:1:0.5) on silica gel to give desired product compound I-44 as a white solid (72 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 1.18-1.25 (m, 4H), 1.47 (br s, 2H), 1.95-1.98 (m, 2H), 2.16-2.18 (m, 2H), 2.34 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 4.02-4.08 (m, 1H), 5.23 (m, 1H), 8.23 (s, 1H). MS: m/z 291.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[C:4]2[N:5]([C:19]([C:22]#[C:23][Si](C)(C)C)=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.CC(OC)(C)C>[C:22]([C:19]1[N:5]2[CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:8]=[C:3]([C:2]([F:1])([F:29])[F:28])[C:4]2=[N:21][CH:20]=1)#[CH:23]
Reactant: C[Si](C)(C)C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CO
Product: C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 0 °C
Reaction time: 6 h
Yield: 65.5 %

Procedure:
To a solution of 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-3-trimethylsilanylethynyl-imidazo[1,2-a]pyridine (10.5 g, 25 mmol) in THF (100 mL) and MeOH (250 mL) at 0° C. was added K2CO3 (340 mg, 10 mol %) and the mixture was stirred at 0° C. for 6 h. Diluted with TBME and ice water, separated, washed with brine, dried over Na2SO4, totally evaporated. Purified by column chromatography (heptane/AcOEt) and trituration with heptane and filtration gave the product as an off-white solid (5.8 g, 66%). MS (ISP) 355.0 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH:17](I)([CH3:19])[CH3:18]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: CC(C)I
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A DMF (15 mL) solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 21.5 mmol) was cooled to 0° C. and then isopropyl iodide (2.57 mL) and Nail (60%, 775 mg, 32.3 mmol) were added under an atmosphere of N2. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned between ether and water, the ether layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (5:95) as eluent to obtain 3-isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (189 mg, 32%) as a solid. 1H NMR (CDCl3, 400 MHz): 7.62 (d, 2H), 7.40 (m, 3H), 6.91 (s, 1H), 3.84 (s, 3H), 1.35 (d, 6H).
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8](=O)[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO>[N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH2:30])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3]
Reactant: [BH3-]C#N
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2C(=O)CC[C@H]1c1cccc(F)c1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (5S,6S)-5-azido-6-(2,3-difluorophenyl)-5,6,7,8-tetrahydro-9H-cyclohepta[b]pyridin-9-one (190 mg, 0.60 mmol), and ammonium acetate (2.3 g, 30 mmol) in MeOH (10 mL) was added sodium cyanoborohydride (27 mg, 0.42 mmol) and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (20 mL) and aqueous 1 N NaOH solution (5 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH:Et3N-100:0:0 to 85:10:5, to give the title compound as a mixture of diastereomers. MS: m/z=316.2 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:12]1[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]>C(OCC)C>[CH2:7]([CH:12]1[CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][CH2:17]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC1CCC(C(=O)O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCC1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a slurry of lithium aluminum hydride (2 equi.) in diethyl ether (4 mL/mmole), a solution of commercially available 4-pentylcyclohexanecarboxylic acid (20) (1 equi.) in diethyl ether (3 ml/mmole) was added at ice temperature over a period of 20 min. The reaction mixture was stirred at room temperature for 24 h, cooled to ice temperature, quenched slowly with water (1 mL/g LAH), 15% aqueous sodium hydroxide (1 mL/g LAH), and water (3 mL/g LAH) consecutively. MgSO4 (5 g/100 mL reaction solution) was added to the reaction mixture, stirred for 30 min, filtered through celite, and concentrated in vacuo to give (4-pentyl-cyclohexyl)-methanol (21) a colorless oil (95%).