Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]2([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1.C(OCC)(=O)C>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([OH:9])([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:10][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C1(COc2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 64.8 %

Procedure:
72.15 g (0.3 mole) of 2-(4-chlorophenoxy-methyl)-2-tert.-butyl-oxirane and 24.15 g (0.35 mole) of 1,2,4-triazole were heated under reflux in 120 ml of ethanol for 48 hours. The mixture was then concentrated, the residue was taken up in 200 ml of ethyl acetate and the ethyl acetate mixture was heated. It was then cooled in an ice bath and the solid was filtered off and rinsed with ethyl acetate. The filtrate was concentrated, the residue was dissolved in ether/hexane and the solution was gassed with hydrogen chloride. The precipitate was filtered off and rinsed with ether and the free base was obtained by adding ethyl acetate/1N sodium hydroxide solution. 60.2 g (65% of theory) of 2-(4-chlorophenoxy-methyl)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol of melting point 84°-87° C. were obtained.
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][N:25]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:12]([NH:11][C:3]2[C:2]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH3:22])=[N:29][CH:28]=3)=[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][N:5]3[N:4]=2)=[O:21])=[CH:15][CH:16]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br
Product: COc1ncc(-c2c(NC(=O)Cc3ccc(F)cc3)nn3cccnc23)cn1

Procedure:
The product from Example 140A and 2-methoxypyrimidine-5-boronic acid were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.69-10.71 (m, 1H), 9.12 (dd, J=6.9, 1.7 Hz, 1H), 8.74 (s, 2H), 8.62 (dd, J=4.1, 1.7 Hz, 1H), 7.30-7.35 (m, 2H), 7.12-7.17 (m, 3H), 3.94 (s, 3H), 3.69 (s, 2H); MS (ESI) m/z 379 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9]Br)([CH3:4])([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH:20]=1)[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:21][C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:20][C:17]=1[CH:18]=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCCOc1ccc(Cl)cc1C=O
Yield: 71.2 %

Procedure:
In a manner similar to the method described in Example 1a, (2-bromo-ethyl)-carbamic acid tert-butyl ester (10 g, 44.8 mmol) was reacted with 5-chloro-2-hydroxy-benzaldehyde (7 g, 44.8 mmol), K2CO3 (18.6 g, 134 mmol) and KI (1.48 g, 8.96 mmol) to give title compound as a oil (9.56 g)
Reaction SMILES: CN(C)C(N(C)C)=N.[C:9]1([C@:15]23[CH2:23][NH:22][CH2:21][C@H:20]2[CH2:19][S:18][C:17]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:16]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:33][C:34]1[CH:35]=[N:36][C:37](Cl)=[N:38][CH:39]=1.O>CS(C)=O>[F:33][C:34]1[CH:35]=[N:36][C:37]([N:22]2[CH2:21][C@@H:20]3[C@@:15]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)([N:16]=[C:17]([NH:24][C:25](=[O:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[S:18][CH2:19]3)[CH2:23]2)=[N:38][CH:39]=1
Reactant: O=C(NC1=N[C@@]2(c3ccccc3)CNC[C@H]2CS1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Agent: CN(C)C(=N)N(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC1=N[C@@]2(c3ccccc3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
N,N,N′,N′-tetramethylguanidine (3.4 mL, 27 mmol) is added to a solution of N-[(4aR,7aS)-7a-phenyl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (7.5 g, 22 mmol) and 5-fluoro-2-chloropyrimidine (3.5 g, 27 mmol) in dimethylsulfoxide (75 mL). The reaction is stirred at 100° C. for 2 hours, cooled to room temperature and water is added (225 mL). The precipitated product is isolated by filtration and is dried in a vacuum oven at 45° C. to give the title compound (9.5 g, 99%). ES/MS (m/e): 434 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[C:16]3[C:15]([NH:17][CH:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:45][S:46]([CH3:49])(=[O:48])=[O:47].FC(F)(F)C(O)=O.N>>[OH:1][C:2]1[C:7]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:45][S:46]([CH3:49])(=[O:47])=[O:48]
Reactant: Cc1ccn2nc(C(C)Nc3ncnc4c3c(-c3cccc(NS(C)(=O)=O)c3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc(NS(C)(=O)=O)c5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 35 %

Procedure:
N-(2-Hydroxy-3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (12 mg, 0.02 mmol) was treated with trifluoroacetic acid (1 ml, 13 mmol) and a solution of ammonia (7N in methanol, 1 ml, 7 mmol) according to the method described in Example 27 to give 4 mg (41% yield) of the title compound. Purity 100%.
Reaction SMILES: Br[Mg][C:3]#[CH:4].[CH3:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11](=[O:13])[CH3:12]>O1CCCC1>[CH3:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]([OH:13])([C:3]#[CH:4])[CH3:12]
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1nccn1C
Solvent: C1CCOC1
Product: C#CC(C)(O)c1nccn1C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed bromo(ethynyl)magnesium (0.5M in THF, 77 mL, 1.20 equiv). This was followed by the addition of a solution of 1-(1-methyl-1H-imidazol-2-yl)ethan-1-one (4.0 g, 32.22 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) dropwise with stirring at 0° C. in 20 min. The resulting solution was stirred for 20 min at 0° C. The resulting solution was allowed to react with stirring for an additional 5 h at room temperature. The reaction was then quenched by the addition of 50 mL of saturated aqueous NH4Cl. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/hexane (1/3) to give 2.8 g (58%) of 2-(1-methyl-1H-imidazol-2-yl)but-3-yn-2-ol as a off-white solid. 1H-NMR (300 MHz, CDCl3, ppm) δ 7.065 (d, 1H), 6.842 (d, 1H), 3.935 (d, 3H), 3.092 (s, 3H), 1.950 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].I[CH3:29]>C1COCC1.C(OCC)(=O)C>[CH3:29][O:1][C:2]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CI
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC

Procedure:
Methyl 2-hydroxy-4-(1-Boc-4-piperidyloxy)benzoate (6.7 g, 19.1 mmol) was dissolved in THF (20 ml) and stirred in an ice bath under nitrogen. Sodium hydride (1.17g of a 60% suspension in mineral oil, 29.5 mmol) was added and the mixture was stirred for 15 min in the cold, then for 15 min at ambient temperature. Iodomethane (2.4 ml, 5.47 g, 38.1 mmol) was added and the mixture was allowed to stir at ambient temperature under nitrogen for 72 hours. An additional 0.51 g of 60% sodium hydride suspension was added and the mixture stirred an additional 7 hours, then an additional 1.2 ml of iodomethane was added and the mixture stirred another 18 hours. An additional 0.53 g of sodium hydride suspension was added, the mixture was stirred 1.5 hours, then an additional 1 ml of iodomethane was added and the mixture stirred 6 hours. An additional 1 ml of iodomethane was added and the mixture stirred 18 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo to give methyl 2-methoxy-4-(1-Boc-4-piperidyloxy)-benzoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([NH:8]CC2C=CC(OC)=C(OC)C=2)=[N:6][CH:7]=1.C(=O)(O)[O-].[Na+].CCCCCC>FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([CH:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: COc1ccc(CNc2cc(C(c3c(F)cccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: Nc1cc(C(c2c(F)cccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 65 °C
Yield: 67.8 %

Procedure:
The 5-chloro-4-[(4-chlorophenylsulfonyl)(2,6-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine (293 mg, 0.506 mmol) obtained in Example 295 was dissolved in trifluoroacetic acid (4 ml). The resulting solution was heated at 65° C. for 2 hours. The reaction mixture was concentrated. The residue thus obtained was basified with a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=2:1 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane to give the title compound (147 mg, 0.343 mmol, 68%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CCO.CC(O)=O.[Fe]>[NH2:12][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cccc(Cl)c1N
Temperature: 25 °C
Yield: 79 %

Procedure:
Iron powder (1.94 g, 34.8 mmol) was added to the solution of methyl 3-chloro-2-nitrobenzoate (2.5 g, 11.6 mmol) in EtOH/HOAc (100 mL/100 mL) at room temperature, and then the suspension was refluxed under N2 for 2 hrs. After cooling down to room temperature, partial of the solvents was removed on rotary vacuum, the resulting residue was partitioned between H2O/EtOAc (200 mL/300 mL). The separated organic phase was washed with aqueous NaOH (1N, 50 mL), brine (50 mL), dried over MgSO4, and concentrated on rotary vacuum to afford the expected product as a tan oil (1.7 g, 79% yield) which became wax type solid standing on bench. The crude product was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 3.86 (s, 3H), 6.25 (s, 2H), 6.57 (t, J=7.93 Hz, 1H), 7.39 (dd, J=7.81, 1.51 Hz, 1H), 7.79 (dd, J=8.06, 1.51 Hz, 1H); Mass spec. 185.95 (MH+), Calc. for C8H8ClNO2 185.02.
Reaction SMILES: [C:1](O[C@@H](C1C(C)=CC2N=C(N3CCN(C)C(C4C=C5C(=CC=4)N(C)N=C5)C3=O)SC=2C=1C1C=CC(Cl)=CC=1)C(O)=O)(C)([CH3:3])[CH3:2].[C:45]([O:49][C@@H:50]([C:56]1[C:80]([CH3:81])=[CH:79][C:59]2[N:60]=[C:61]([N:63]3[CH2:68][CH2:67][NH:66][CH:65]([C:69]4[CH:70]=[C:71]5[C:75](=[CH:76][CH:77]=4)[N:74]([CH3:78])[N:73]=[CH:72]5)[CH2:64]3)[S:62][C:58]=2[C:57]=1[C:82]1[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][CH:83]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])([CH3:48])([CH3:47])[CH3:46].COC(OC)(C)C.C=O>CC(C)=O>[C:45]([O:49][C@@H:50]([C:56]1[C:80]([CH3:81])=[CH:79][C:59]2[N:60]=[C:61]([N:63]3[CH2:68][CH2:67][N:66]([CH:1]([CH3:3])[CH3:2])[CH:65]([C:69]4[CH:70]=[C:71]5[C:75](=[CH:76][CH:77]=4)[N:74]([CH3:78])[N:73]=[CH:72]5)[CH2:64]3)[S:62][C:58]=2[C:57]=1[C:82]1[CH:87]=[CH:86][C:85]([Cl:88])=[CH:84][CH:83]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52])([CH3:46])([CH3:47])[CH3:48]
Reactant: Cc1cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Agent: C=O
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1

Procedure:
(2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(4-isopropyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (16 mg) was prepared in a similar manner as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid except using (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetate, and acetone and 2,2-dimethoxypropane instead of (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid and formaldehyde. LCMS-ESI+: calc'd for C37H45ClN5O3S: 674.3 (M+H+); Found: 674.3 (M+H+).
Reaction SMILES: [C:1]1([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([OH:25])=O)[CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:26]CCl>CN(C)C=O>[C:1]1([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]([Cl:26])=[O:25])[CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2cccc3ccccc23)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a suspension of 3-[3-(naphthalen-1-ylsulfamoyl)-phenyl]-acrylic acid (15d) (0.22 g, 0.62 mmol) in dichloromethane (2.5 ml) oxalyl chloride (0.16 ml, 1.86 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.23 g, 99%).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][N:32]([CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1)[CH3:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CNCC1CCCN1C(=O)OC(C)(C)C
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1)CC1CCCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (420 mg) and 2-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (310 mg) in acetonitrile (10 mL) was added potassium carbonate (250 mg). The reaction mixture was heated at 80° C. for 4 h and then allowed to cool to room temperature. The mixture was then partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL) and the organic layer washed with brine (20 mL), dried (MgSO4), reduced in vacuo and purified on column chromatography to give 2-{[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid (487 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[K+].[F:14][C:15]([F:22])([F:21])[C:16]([F:20])=[C:17]([F:19])[F:18]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:17]([F:19])([F:18])[CH:16]([F:20])[C:15]([F:22])([F:21])[F:14])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: FC(F)=C(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OC(F)(F)C(F)C(F)(F)F)cc1

Procedure:
456 g (3 moles) of 4-hydroxybenzoic acid methyl ester, 30 g of 85% potassium hydroxide, and 1 l of acetone were placed in an autoclave. An amount of 562.5 g (3.75 moles) of hexafluoropropylene was introduced under pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13](OCC)=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][C:3]=1[F:18].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[CH:11][O:10][N:9]=2)=[CH:4][C:3]=1[F:18]
Reactant: CCOC(=O)c1conc1-c1ccc(Cl)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1conc1-c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 3-(4-chloro-3-fluorophenyl)isoxazole-4-carboxylate (12.00 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 100 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-(4-chloro-3-fluorophenyl)-4-isoxazolylmethanol (9.75 g, yield 96%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 124–125° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[Br:11]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:11][C:6]1[C:7]([NH2:10])=[N:8][CH:9]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: Nc1ccc(C2CC2)cn1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ncc(C2CC2)cc1Br
Reaction time: 18 h

Procedure:
To a solution of 5-cyclopropyl-pyridin-2-ylamine (1.1 g, 8.19 mmol) in dry chloroform (100 mL) was added bromine (0.42 mL, 8.2 mmol) in chloroform (11 mL) at room temperature and stirred for 18 hours. An aqueous solution of sodium thiosulfate was added, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/hexane as eluent. The title compound was obtained as light yellow oil (1.0 g, 57%).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][N:8]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH:1]1([CH:7]2[CH2:12][C:11]([OH:13])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:10][CH2:9][N:8]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C(C2CCCCC2)C1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2)CC1C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Benzyl 2-cyclohexyl-4-oxopiperidine-1-carboxylate in THF (155 ml) was cooled to 0° C. and added phenylmagnesium bromide (22.08 ml, 61.8 mmol). The ice bath was removed and the solution stirred at room temperature for 14 hours. Quenched the reaction with 1N HCl and concentrated. Extracted three times with EtOAc and washed twice with water. The organics were dried, concentrated, and purified on silica gel 30% EtOAc.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH3:10][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH3:10])=[CH:4][N:3]=1
Reactant: Cc1ncc(C=O)cn1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ncc(C(C)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-methylpyrimidine-5-carbaldehyde (5.00 g, 38.9 mmol) in tetrahydrofuran (85 mL) was slowly added 33 mL of 1.4 M methylmagnesium bromide solution in tetrahydrofuran at 0° C. The mixture was stirred at room temperature for 1 hour and then quenched with water (50 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCOP(=O)(CCC#N)c1ccccc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOP(=O)(CCCN)c1ccccc1

Procedure:
To 22.72 g of ethyl 2-cyanoethyl(phenyl)phosphinate in 400 ml of ethanol are added 34 g of liquid ammonia and 4.5 g of Raney-Nickel. The mixture is heated to 80° and treated with hydrogen at 100 bar. After 30 minutes hydrogen up-take stops. The reaction mixture is filtered and the filtrate distilled to give ethyl 3-aminopropyl(phenyl)phosphinate as a colorless oil, b.p. 110°/13 Pa.
Reaction SMILES: [N:1]1([C:6]2([CH2:12][CH2:13][OH:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:16]1[S:17][C:18]([Br:21])=[CH:19][N:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:21][C:18]1[S:17][C:16]([N:9]2[CH2:8][CH2:7][C:6]([CH2:12][CH2:13][OH:14])([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:11][CH2:10]2)=[N:20][CH:19]=1
Reactant: OCCC1(N2CCCC2)CCNCC1
Reactant: Brc1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCC1(N2CCCC2)CCN(c2ncc(Br)s2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
A mixture of 2-(4-pyrrolidine-1-ylpiperidine-4-yl)ethanol (4.11 g), 2,5-dibromothiazole (5.03 g), potassium carbonate (3.43 g) and dimethylformamide (75 mL) was stirred at 60° C. for 16 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and washed with magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (3.88 g). Yield: 52%.