Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42](F)(=[O:44])=[O:43]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[F:35])(=[O:44])=[O:43])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(F)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3C(=O)OC(C)(C)C)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(S(=O)(=O)c2ccccc2F)n3C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 42.9 %

Procedure:
To a −75° C. solution of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-indole-1-carboxylic acid tert-butyl ester 2 (500 mg, 1.25 mmol) in THF (25 mL) was slowly added t-BuLi (1.47 mL, 2.5 mmol). The reaction mixture was stirred for 30 minutes at which time 2-fluoro-benzenesulfonyl fluoride 2a (222 mg, 1.5 mmol) was added. The reaction was stirred for 1.5 h at which time the ice bath was removed and the reaction was allowed to warm over 45 min. The reaction mixture was quenched with a saturated solution of ammonium chloride (55 mL). The mixture was then extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers were washed with brine (25 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. The oil was chromatographed over silica eluting with hexane:ethyl acetate (17:3) to afford 300 mg (43%) of 4-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-(2-fluoro-benzenesulfonyl)-indole-1-carboxylic acid tert-butyl ester (1-3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][O:21][CH2:20]2)[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].[Cl:24][C:25]1[C:35]2[O:34][CH2:33][CH2:32][N:31]([CH3:36])[C:30](=[O:37])[C:29]=2[CH:28]=[CH:27][C:26]=1F>>[Cl:24][C:25]1[C:35]2[O:34][CH2:33][CH2:32][N:31]([CH3:36])[C:30](=[O:37])[C:29]=2[CH:28]=[CH:27][C:26]=1[O:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([O:18][C@H:19]2[CH2:23][CH2:22][O:21][CH2:20]2)[CH:17]=1)[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6]
Reactant: CN1CCOc2c(ccc(F)c2Cl)C1=O
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)cn1
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3Cl)OCCN(C)C4=O)cc(O[C@H]3CCOC3)c2)cn1

Procedure:
The preparations of 3-hydroxy-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide and 9-chloro-8-fluoro-4-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one were described earlier.
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:16]=[C:15]([O:30][CH3:31])[N:14]=2)[CH:8]=1)[CH3:4].O.[NH2:35]N>C(O)(=O)C>[CH3:31][O:30][C:15]1[N:16]=[C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:18]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[NH:35][N:2]=[C:3]([CH3:4])[N:5]=3)[CH:8]=2)[N:14]=1
Reactant: NN
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(=O)N=C(C)N(C)C)c3)nc(OC)n2)cc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(-c4nc(C)n[nH]4)c3)nc(OC)n2)cc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of N-(1-dimethylamino-ethylidene)-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzamide [0.132 mmol, Intermediate (46)] and hydrazine hydrate (15 μL, 0.48 mmol) in acetic acid (1 mL) is heated to 90° C. After stirring for 30 minutes removed from heat, quenched with saturated sodium bicarbonate solution (20 mL) and extracted twice with EtOAc (20 mL). The organic extracts are dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting oil is subjected to flash column chromatography on silica gel eluting with 40% EtOAc in heptane gradient to afford {2-methoxy-6-[3-(5-methyl-2H-[1,2,4]triazol-3-yl)-phenyl]-pyrimidin-4-yl}-[2-(4-methoxy-phenyl)-ethyl]-amine [38 mg, 69%, Example 37]. LCMS: RT=2.59 minutes MS: 417 (M+H). IC50=3.7 nM
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][S-:11].[Na+].CCOC(C)=O>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([S:11][CH3:10])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: C[S-]
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (1.0 g, 6.1 mmol) in EtOH (15 ml) was added sodium thiomethoxide (0.43 g, 6.10 mmol) and the reaction mixture was stirred for 1 hour at room temperature. The mixture was poured onto water and EtOAc. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the crude title compound (910 mg) as a yellow solid. LC-MS (ES) m/z=176 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]#[N:10])=[CH:4][CH:3]=1.[C:17]1(B(O)O)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH:11]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[C:26]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:22]=[CH:23][CH:24]=3)=[CH:3][CH:4]=2)[C:9]#[N:10])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: N#CC(c1ccc(Br)cc1)C1CCCCC1
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: Cc1ccccc1
Product: N#CC(c1ccc(-c2cccc3ccccc23)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of Example 1A (3.0 g, 10.8 mmol), 1-naphthylboronic acid (2.04 g, 11.9 mmol), Pd(PPh3)4 (249 mg, 0.22 mmol), and 3M Na2CO3 (9.0 mL, 27 mmol) in toluene (18 mL) was heated to 100° C. in a sealed tube, stirred for 14 hours, cooled to room temperature, and partitioned between water and diethyl ether. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20:1 to 10:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: Cl.[CH:2]([O:5][C:6](=[O:11])[C@@H:7]([CH2:9][OH:10])[NH2:8])([CH3:4])[CH3:3].[NH:12](C(OCC1C=CC=CC=1)=O)[C@H:13]([C:25](O)=[O:26])[CH2:14][C:15](=[O:24])[O:16]CC1C=CC=CC=1>>[CH:2]([O:5][C:6](=[O:11])[C@@H:7]([CH2:9][OH:10])[NH:8][C:25](=[O:26])[C@H:13]([CH2:14][C:15](=[O:16])[OH:24])[NH2:12])([CH3:4])[CH3:3]
Reactant: CC(C)OC(=O)[C@H](N)CO
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Cl
Product: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@@H](N)CC(=O)O

Procedure:
This compound was prepared from 1.8 g D-serine isopropyl ester hydrochloride and 3.6 g Z-Asp(OBzl) in a manner similar to Example 16 (A). Yield: 1.9 g.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1.ClCCl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O>[CH:2]([C@H:3]1[O:8][C:7]([CH3:9])([CH3:10])[O:6][C@@H:5]([CH2:11][C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])[CH2:4]1)=[O:1]
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C[C@H]1C[C@@H](C=O)OC(C)(C)O1
Reaction time: 5 h
Yield: 86.7 %

Procedure:
2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide (5.0 g), dichloromethane (30.0 mL), and Dess-Martin periodinane (11.2 g) were added to a reactor under nitrogen atmosphere. The reaction mixture was stirred at 20˜30° C. for over 5 hours. Water (30.0 mL) was added to the reaction mixture. The separated organic layer was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1:3) to obtain 2-[(4R,6S)-6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl]-N-methoxy-N-methyl-acetamide as a white solid (4.3 g, yield 87%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br)([O-:16])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)([O-:16])=[O:15]
Reactant: COC(=O)c1ccc2c(c1)CCN2
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc2c(c1)CCN2Cc1cccc([N+](=O)[O-])c1

Procedure:
A mixture of the indoline (Example 31) (4.39 g), 3-nitrobenzyl bromide (5.02 g) and anhydrous potassium carbonate (3.17 g) in methylethylketone (150 ml) was heated under reflux for 18 hours. On cooling, the inorganics were filtered off and the solvent removed in vacuo. The reaction mixture was extracted from water into ethyl acetate, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with chloroform, gave methyl 1-(3-nitrobenzyl)indoline-5-carboxylate, m.p. 99°-100° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.B(OC(C)C)(OC(C)C)[O:19]C(C)C.C([Li])CCC.Cl>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:12]([C:11]3[CH:10]=[CH:9][C:8]([OH:19])=[CH:7][C:6]=3[C:5]2([CH3:17])[CH3:16])=[CH:13][CH:14]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)c2cc(O)ccc2-c2ccc(Br)cc21
Reaction time: 2 h

Procedure:
21.2 g (58.6 mmol) of 2,7-dibromo-9,9-dimethyl-9H-fluorene (CAS No. 28320-32-3) and 19.0 ml (82.8 mmol) of triisopropyl borate are dissolved in 500 ml of THF, and 56 ml (89 mmol) of a 15 percent solution of n-butyllithium in n-hexane are added at −70° C. After 2 h, 200 ml of 2 M hydrochloric acid are added, and the batch is allowed to thaw at room temp. and extracted three times with MTB ether. The combined org. phases are dried over sodium sulfate, the solvent is removed in vacuo, and the residue is taken up in 400 ml of toluene. After addition of 85 ml of 2 M sodium hydroxide solution, 15.5 ml of 30 percent hydrogen peroxide are added with vigorous stirring at such a rate that the temp. does not exceed 40° C. When the addition is complete, the batch is stirred for a further 30 min, added to 500 ml of water and acidified using 2 M hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with dil. ammonium iron(II) sulfate soln. and water, dried over sodium sulfate and evaporated. Filtration of the crude product through silica gel with toluene/ethyl acetate (9:1) gives 7-bromo-9,9-dimethyl-9H-fluoren-2-ol as colourless solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH3:11])[C:3]=1[C:12]#[N:13].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[C:12]([C:3]1[C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:13]
Reactant: COC(=O)c1sc(Br)c(C#N)c1C
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1C
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A mixture of methyl 5-bromo-4-cyano-3-methylthiophene-2-carboxylate (6.29 g, 24.2 mmol), morpholine (2.53 g, 29.0 mmol) and cesium carbonate (15.8 g, 48.4 mmol) in anhydrous Tetrahydrofuran (110 mL) was heated to reflux for 19 hours, and then cooled to room temperature. The mixture was filtered and washed with DCM. The filtrate was rotavaped with Celite. The coated Celite was dry loaded in a silica gel cartridge and chromatographed using MeOH/DCM (1/99) to give a white solid product (4.70 g, yield 73%). LC/MS: (FA) ES+ 267. 1H NMR (400 MHz, d-chloroform) δ 3.85 (m, 4H), 3.82 (s, 3H), 3.58 (m, 4H), 2.56 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:12])[CH2:8][CH:9]([CH3:11])[CH3:10].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27]Cl>CS(C)=O.O>[CH2:7]([NH:12][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1)[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCN
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CCNCCCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and isoamylamine (0.21 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(isoamyl)-(4-(naphthalen-2-yloxy)-butyl)amine, solid, m.p. 102° C., (yield 0.54 gm, 89.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH2:45][CH2:46][CH2:47]Br)[CH:39]=1)(=[O:36])[CH3:35]>CN(C=O)C>[C:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH2:45][CH2:46][CH2:47][O:26][C:23]2[CH:22]=[CH:21][C:20]([CH2:19][CH2:18][N:14]3[CH2:13][C@@H:12]([C:10]4[CH:9]=[CH:8][C:6]5[O:7][C:2]([CH3:27])([CH3:1])[O:3][CH2:4][C:5]=5[CH:11]=4)[O:16][C:15]3=[O:17])=[CH:25][CH:24]=2)[CH:39]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Oc1cccc(CCCCBr)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(O)cc4)C(=O)O3)ccc2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(CCCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-[2-(4-hydroxyphenyl)ethyl]-1,3-oxazolidin-2-one (Example 28 v) (37 mg) in dry DMF (0.4 mL) was treated with caesium carbonate (65 mg) and 3-(4bromobutyl)phenyl acetate (0.2 mmol) as a solution in DMF (0.5 mL). Further DMF was added (1 mL) and the reaction mixture stirred at 50° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo in a genevac. The residue was suspended in chloroform and filtered to remove inorganic salts. The filtrate was added to the top of a pre-conditioned NH2 propyl cartridge (1 g). The cartridge was washed with chloroform and methanol and the title compound eluted with 2M NH3-MeOH. LCMS RT=3.86 min
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:20]2[CH2:25][CH2:24][N:23]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: C1CCCC(N2CCNCC2)CC1
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CCCCCC2)CC1

Procedure:
This example was prepared according to Example 1 by employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-cycloheptylpiperazine, which is commercially available from, for example, Sigma-Aldrich. m/z (ES+) M+1=327.2; HPLC tR=1.90 min. 1H NMR (500 MHz, CDCl3) □7.26 (m, 2H), 7.22-7.13 (m, 1H), 7.09 (d, J=6.7 Hz, 2H), 3.86-3.50 (m, 4H), 2.60-2.42 (m, 6H), 1.95 (dt, J=5.1, 3.8 Hz, 1H) 1.83-1.73 (m, 2H), 1.71-1.60 (m, 3H), 1.58-1.31 (m, 8H), 1.24 (ddd, J=8.2, 6.1, 4.3 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25](I)[CH:24]=[CH:23][C:22]=1[OH:28]>C(Cl)Cl>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[C:25]([C:2]#[C:1][C:3]2([CH3:17])[CH2:8][CH2:7][C:6]3[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=3[O:4]2)[CH:24]=[CH:23][C:22]=1[OH:28]
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: COC(=O)c1cc(I)ccc1O
Solvent: ClCCl
Product: COC(=O)c1cc(C#CC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)ccc1O

Procedure:
rac-5-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)ethynyl]-2-hydroxybenzoic acid methyl ester was prepared by reacting rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with 2-hydroxy-5-iodobenzoic acid methyl ester [M. Covello, Chim. Ther. 2, 73 (1967)] as described in Example 4. The compound was isolated by chromatography over silica gel using methylene chloride and was crystallized from ethyl acetate/hexane to yield colorless crystals with m.p. 151°-153° C.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)([OH:16])N.Cl([O-])=O.[Na+]>CC(C)=O.O.O>[C:1]1([C:7]2[CH:8]=[C:9]([C:12]([OH:16])=[O:13])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1cc(-c2ccccc2)cs1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)cs1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
4-phenyl-thiophene-2-carboxaldehyde (150 mg, 0.80 mmol) was dissolved in acetone-water mixture (2:1) (3 mL) and cooled to 0° C. To this reaction mixture was added sulphamic acid (232 mg, 2.38 mmol) and sodium chlorite (288 mg, 3.18 mmol) dissolved in minimum amount of water. The resulting reaction mixture was allowed to stir at room temperature for half an hour. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulphate and concentrated to afford 100 mg (62.5% yield) of 4-Phenyl-thiophene-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[CH2:32]([O:31][C:29](=[O:30])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:16]=2[O:15]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccccc1-c1cccc2c1OC(CN)C2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 85.1 %

Procedure:
Treatment of (±)-[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (3.55 g, 12.9 mmol) with diisopropylethylamine (2.5 g, 19.4 mmol) and benzyl chloroformate (2.42 g, 14.2 mmol) generally according to the procedure described for Intermediate 12 provided 4.1 g (85%) of (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a clear oil Rf=0.64 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C24H23F4NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.95; H, 6.18; N, 3.53. Chiral HPLC separation of (±)-benzyl[7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, isopropanol:hexane 1:4) provided two fractions. Fraction 1 (Rt=7.285 min, isopropanol:hexane 1:4); Fraction 2 (Rt=9.361 min, Chiralcel OD, isopropanol:hexane 1:4).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[CH3:15][C:16]([CH3:27])([CH2:25][CH3:26])[CH2:17][C:18]1[N:19]=[C:20]([CH3:24])[N:21]([OH:23])[CH:22]=1>C(Cl)Cl>[CH3:15][C:16]([CH3:27])([CH2:25][CH3:26])[CH2:17][C:18]1[N:19]=[C:20]([CH3:24])[N:21]([O:23][S:10]([N:9]([CH3:14])[CH3:8])(=[O:12])=[O:11])[CH:22]=1
Reactant: CCC(C)(C)Cc1cn(O)c(C)n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(OS(=O)(=O)N(C)C)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Triethylamine (100 mL, 0.72 mol) followed by N,N-dimethylsulfamoyl chloride (42 mL, 0.38 mol) were added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazol-1-ol in methylene chloride (100 mL). After stirring at ambient temperature for 2 h, the reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography over silica eluting with ethyl acetate/hexane followed by methanol afforded N-({[4-(2,2-dimethylbutyl)-2-methyl-1H-imidazol-1-yl]oxy}sulfonyl)-N-methylmethanamine (ca. 50% purity by HPLC) which was dissolved in 7:1 methanol/acetic acid (400 mL), and 10% Palladium (10% on activated carbon) (6 g) was added. After stirring under 40 psi hydrogen for 2 h, the reaction mixture was filtered through celite, rinsing with methanol and concentrated in vacuo. The residue was redissolved in ethyl acetate and washed with 1 N aqueous sodium hydroxide and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 5-20% methanol/methylene chloride afforded 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazole.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].Cl.Cl.[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:18]([C:20]3[CH:21]=[C:22]([Cl:33])[C:23]([C:31]#[N:32])=[C:24]4[C:30]=3[O:29][CH2:28][CH2:27][NH:26][CH2:25]4)[CH3:19])[N:15]=[C:16]([CH3:17])[C:9]=12.C(N(CC)CC)C>CN(C)C=O>[NH2:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]2[N:14]([CH:18]([C:20]3[CH:21]=[C:22]([Cl:33])[C:23]([C:31]#[N:32])=[C:24]4[C:30]=3[O:29][CH2:28][CH2:27][N:26]([CH2:2][CH2:3][OH:4])[CH2:25]4)[CH3:19])[N:15]=[C:16]([CH3:17])[C:9]=12
Reactant: OCCBr
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCNC3)c2ncnc(N)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OCCN(CCO)C3)c2ncnc(N)c12
Temperature: 80 °C
Yield: 479.4 %

Procedure:
2-Bromoethanol (4.7 μL, 0.066 mmol) was added to a mixture of 9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (15 mg, 0.039 mmol) (from Example 46, step 13) and triethylamine (10 μL, 0.09 mmol) in N,N-dimethylformamide (2 mL). The reaction was heated at 80° C. for 3 h and then allowed to cool. The product was purified without workup by prep HPLC on a C-18 column eluting water:acetonitrile gradient buffered pH 10 to give the desired compound as white amorphous solid (0.08 g, 50%). LCMS calculated for C20H23ClN7O2 (M+H)+: m/z=428.1; found: 428.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([C:21]([NH2:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29].O>N1C=CC=CC=1>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][C:11]2[C:20]3[C:15](=[C:16]([C:21]([NH2:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1)=[O:29]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C(=O)Nc2cccc([C@@H](C)Nc3ncnc4c(C(N)=O)cccc34)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
A suspension of 4-{[(1R)-1-(3-aminophenyl)ethyl]amino}quinazoline-8-carboxamide (2.0 g, 6.51 mmol) in dry pyridine (50 mL) was treated with 3-fluoro-4-methoxybenzoyl chloride (1.51 g, 8.01 mmol, 1.23 eq), and the contents were stirred at room temp for 45 min. The clear-yellow solution was slowly added to water (1000 mL), and the white precipitate was filtered, washed with water (300 mL) and dried under vacuum at 35° C. to get the title compound in 98% yield (2.93 g).