Azzindani/Open_Reaction_Data huggingface dataset:
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][N:21]([CH3:24])[C:20]2=[O:25])[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].Br[C:27]1[CH:28]=[CH:29][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:24][N:21]1[CH2:22][CH2:23][C@H:19]([O:18][C:16]2[CH:15]=[C:4]([CH:3]=[C:2]([O:1][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:17]=2)[C:5]([NH:7][C:8]2[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=2)=[O:6])[C:20]1=[O:25]
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Reactant: CS(=O)(=O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 40 %

Procedure:
A mixture 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 18) (305 mg, 0.6 mmol), 5-bromo-2-methylsulfonyl-pyridine (CAS no. 98626-95-0) (142 mg, 0.6 mmol), cesium carbonate (390 mg, 1.2 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (112 mg, 0.12 mmol) in N,N-dimethylacetamide (5 mL) was stirred in the microwave at 160° C. for 6 hours. N,N-Dimethylacetamide was removed by evaporation under reduced pressure. The residue was partitioned between ethyl acetate (30 mL) and water (50 mL). The organic phase was separated and the aqueous layer was acidified with hydrochloric acid (1N, 5 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with 0-5% methanol in DCM to afford the product (120 mg, 40%). 1H NMR δ (300 MHz, CDCl3) 2.14-2.32 (m, 1H), 2.52-2.69 (m, 1H), 2.55 (s, 3H), 2.94 (s, 3H), 3.23 (s, 3H), 3.35-3.59 (m, 2H), 4.96 (t, 1H), 7.05 (s, 1H), 7.27 (s, 1H), 7.48 (d, 1H), 7.54 (s, 1H), 8.07 (d, 1H), 8.14 (s, 1H), 8.49 (s, 1H), 8.55 (s, 1H), 9.51 (s, 1H); m/z 498 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4([NH:41]C(=O)OC(C)(C)C)[CH2:40][CH2:39][CH2:38]4)=[CH:33][CH:32]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][C@@H:24]([CH2:28][OH:29])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:49].O1CCOCC1>C(Cl)Cl>[ClH:49].[ClH:49].[ClH:49].[NH2:41][C:37]1([C:34]2[CH:35]=[CH:36][C:31]([N:30]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([N:22]6[CH2:27][CH2:26][O:25][C@@H:24]([CH2:28][OH:29])[CH2:23]6)[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:32][CH:33]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(N6CCO[C@@H](CO)C6)c5)nc43)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCO[C@@H](CO)C4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.7 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[(2R)-2-(hydroxymethyl)morpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (5.20 mg, 0.00803 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixute and stirred at room temperature for 15 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (4.36 mg, 82.7%) as yellow solid.
Reaction SMILES: S(S([O-])=O)([O-])(=O)=[O:2].[Na+].[Na+].[C:10]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=NO)[CH3:24])=[CH:18][CH:17]=1)([O:12][CH3:13])=[O:11].Cl>O.CO>[C:10]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](=[O:2])[CH3:24])=[CH:18][CH:17]=1)([O:12][CH3:13])=[O:11]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: COC(=O)COc1ccc(CC(C)=NO)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)=O)cc1

Procedure:
Sodium metabisulphite (26 g) in water (60 ml) was added to 1-(4-carbomethoxymethoxyphenyl)propan-2-one oxime (7.5 g) in methanol (50 ml) and the mixture refluxed for 6 hours. The reaction mixture was cooled, concentrated hydrochloric acid (30 ml) added and the mixture extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water followed by sodium bicarbonate solution. The ethyl acetate layer was dried (MgSO4) and evaporated to give the title compound as an oil which crystallised on standing, (mp 63°-70°l ). τ (CDCl3) 7.91 (3H, s), 6.30 (2H, s), 6.26 (3H, s), 5.42 (2H, s), 3.17 (2H, d, J=8 Hz), 2.87 (2H, d, J=8 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:8]
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: O=C=NC(=O)c1ccccc1
Solvent: C1COCCO1
Product: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (example 4b) (25 g, 164.5 mmol) in 1.4-dioxane (600 mL) was added benzoyl isocyanate (24.2 g, 164.5 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1.4-dioxane (20 mL×3), and dried under vacuum at 40° C. for 3 hours to give N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide (44.35 g, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ2.10 (s, 3H), 2.24 (s, 3H), 7.52-7.56 (m, 2H), 7.64-7.69 (m, 1H), 8.01-8.03 (m, 2H), 11.57 (brs, 1H), 12.05 (brs, 1H). MS 300 (MH+).
Reaction SMILES: C#C.[CH2:3]([Li])[CH2:4]CC.C(O[C@@H:12]1[C@H:17]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C:14](=[O:33])[CH2:13]1)[C@:26]1([CH3:27])[C:21]([CH:22]=[C:23]([O:31]C)[CH2:24][CH2:25]1)=[CH:20][CH2:19]3)(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:3]([C@:14]1([OH:33])[CH:13]=[CH:12][C@H:17]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:15]12[CH3:16])[C@:26]1([CH3:27])[C:21](=[CH:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)#[CH:4]
Reactant: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reactant: [Li]CCCC
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 2 h

Procedure:
Acetylene is introduced at 0° C. for 45 minutes into 200 ml of butyllithium solution (1.6 molar in hexane) in 600 ml of tetrahydrofuran. Then 20.0 g of 15α-acetoxy-3-methoxyandrosta-3,5-dien-17-one in 400 ml of tetrahydrofuran is added thereto. After 2 hours, the mixture is gently combined with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, dried, and concentrated under vacuum. At room temperature, 14 ml of concentrated hydrochloric acid is added dropwise to the crude product in 400 ml of methanol and 50 ml of water. After 1.5 hours, the reaction mixture is stirred into ice/water. The thus-precipitated product is suctioned off, washed with water, dissolved in ethyl acetate, dried, and concentrated under vacuum. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, thus obtaining 9.5 g of 17α-ethynyl-17β-hydroxyandrosta-4,15-dien-3-one, mp 206.4° C. (from acetone/hexane).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>O1CCOCC1>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:20]=[CH2:21])[C:3]1=[O:19]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O

Procedure:
100 g (308 mmol) of the compound from Example 28A are dissolved in 1.4 l of anhydrous dioxane, and 8.9 g (7.7 mmol) of tetrakis(triphenylphospine)palladium and 117 g (370 mmol) of tributylvinyltin are added. The mixture is heated at reflux for 16 h. The reaction solution is then allowed to cool and filtered through kieselguhr. The filtrates are concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. Petroleum ether is added until crystallization sets in. The crystals are filtered off and dried under reduced pressure. This gives 37 g (41% of theory) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][N:8]([C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][O:14]3)=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.O1CCOCC1C=O.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:38]=2[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40])[C:33]([Cl:50])=[CH:32][N:31]=1>>[Cl:50][C:33]1[C:34]([NH:36][C:37]2[C:48]([F:49])=[CH:47][CH:46]=[CH:45][C:38]=2[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40])=[N:35][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[CH2:6][CH2:7][N:8]([C:11]([CH:13]4[CH2:18][O:17][CH2:16][CH2:15][O:14]4)=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:31][CH:32]=1
Reactant: Nc1ccc2c(c1)CCN(C(=O)C1COCCO1)CC2
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: O=CC1COCCO1
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)C2COCCO2)CC3)ncc1Cl

Procedure:
(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone, prepared in a similar manner as 7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone of Example 633b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[3-([1,4]dioxane-2-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-prop-2-ynyl-benzamide as a lyophylate (18%); 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 9.19 (d, J=8.44 Hz, 1H), 8.97 (m, 1H), 8.17 (s, 1H), 7.52-7.45 (m, 3H), 7.25 (s, 1H), 7.15 (m, 1H), 6.87 (m, 1H), 4.38 (m, 1H), 4.01 (m, 2H), 3.84-3.3 (bm, H2O+11H), 3.11 (s, 1H), 2.81 (m, 1H), 2.67 (m, 2H); MS (m/e) 579.16 (M+H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:10](=[O:11])[C:9]2([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]2)[N:8](C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)(O)=[O:2].[NH2:33][C:34]1[CH:35]=[C:36]2[C:49](=[CH:50][CH:51]=1)[CH2:48][C@@:38]1([C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][C:39]1=[O:47])[CH2:37]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C>[F:31][C:29]1[CH:30]=[C:25]([C@H:6]2[N:5]([CH2:4][C:1]([NH:33][C:34]3[CH:35]=[C:36]4[C:49](=[CH:50][CH:51]=3)[CH2:48][C@@:38]3([C:46]5[C:41](=[N:42][CH:43]=[CH:44][CH:45]=5)[NH:40][C:39]3=[O:47])[CH2:37]4)=[O:2])[C:10](=[O:11])[C:9]3([CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12]3)[NH:8][CH2:7]2)[CH:26]=[C:27]([F:32])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Reactant: Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)C2(COCCOC2)NC[C@H]1c1cc(F)cc(F)c1)Nc1ccc2c(c1)C[C@]1(C2)C(=O)Nc2ncccc21

Procedure:
0.114 g (0.25 mmol) tert-butyl (R)-4-carboxymethyl-3-(3,5-difluoro-phenyl)-5-oxo-8,11-dioxa-1,4-diaza-spiro[5.6]dodecane-1-carboxylate were stirred overnight at RT with 67.9 mg (0.27 mmol) (S)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 63.3 mg (0.33 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 44.6 mg (0.33 mmol) HOBT, 35 μl (0.25 mmol) TEA and 1.5 ml DMF. The solvent was spun off and the residue was stirred with 15 ml of a methanolic hydrochloric acid (1.25N) 1 h at 50° C. The reaction mixture was concentrated by rotary evaporation and the residue was purified by PR-HPLC. The product-containing fractions were concentrated by rotary evaporation and the residue was triturated with diisopropylether. After suction filtering the solid was washed with diisopropylether and dried.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]([CH2:29][CH3:30])[C:21](=[O:28])[CH:22]([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:33](I)[CH2:34][CH2:35][CH3:36]>C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]([CH2:29][CH3:30])[C:21](=[O:28])[C:22]([CH2:33][CH2:34][CH2:35][CH3:36])([CH3:27])[C:23](=[O:26])[N:24]([CH3:25])[C:18]=2[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCN1C(=O)C(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc21
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC1(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc2N(CC)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Under ice cooling, sodium hydride (60% in oil) (129 mg, 3.23 mmol) was added to a N,N-dimethylformamide (5 mL) solution of 7-benzyloxy-1-ethyl-3,5-dimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (500 mg, 1.48 mmol), and the mixture was stirred at 0° C. for 30 minutes. Thereafter, butyl iodide (0.336 mL, 2.95 mmol) was added. The reaction solution was stirred at 0° C. for 30 minutes, and then stirred at room temperature for 2 hours. The reaction solution was poured into ice water, and ethyl acetate (20 mL) extraction was performed. The resulting organic layer was washed with water, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (elution solvent: 1:2=ethyl acetate:n-hexane). The solvent was distilled off, thereby obtaining 520 mg of a colorless, liquid target compound (yield: 89%).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14])=O)C1C=CC=CC=1.[H][H]>CO>[NH2:11][C@@H:12]([CH2:17][N:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)[C@H](CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Solvent: CO
Product: COC(=O)[C@@H](N)CN(c1ccccc1)c1ccccc1
Yield: 91 %

Procedure:
In order to eliminate the Z protecting group, 2.7 g (6.68 mmol) of the Z-protected derivative (10) were dissolved in 500 ml of methanol, and 100 mg of catalyst (10% Pd(OH)2—C) were supplied under a protective atmosphere of nitrogen. The inert gas was then displaced with a large excess of hydrogen and the mixture was shaken for 2 h in the hydrogen atmosphere. In order to terminate the reaction, the catalyst was filtered off and the filtrate was concentrated. 1.65 g (yield: 91%) of methyl 2-amino-3-diphenylaminopropionate (11) were obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8](N)[C@@H:7]([O:13][CH3:14])[CH2:6]2.ClC1C=C2C(=CC=1)C(=[O:25])CC2.COC(OC)OC.CC1C=CC(S(OI(O)C2C=CC=CC=2)(=O)=O)=CC=1>>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:25])[CH:7]([O:13][CH3:14])[CH2:6]2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1N
Agent: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Agent: Cl
Solvent: COC(OC)OC
Product: COC1Cc2cc(Cl)ccc2C1=O

Procedure:
Scheme 3 describes the preparation of (1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (20) which is further exemplified in Example 4 below. 5-chloro-2,3-dihydro-1H-inden-1-one (17) was reacted with trimethylorthoformate under acidic conditions, followed by treatment with Koser's reagent [PhI(OH)(OTs)] to give 5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-one (18). The indenone was treated with (R)-tert-butyl sulfinamide in the presence of titanium tetraethoxide to afford the corresponding sulfinamide (19). The reaction was allowed to proceed until less than 5% of the undesired diastereoisomer could be detected by HPLC. The crude sulfinamide was reduced using NaBH4 to afford the primary amine which was treated with hydrochloric acid to afford (1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-amine hydrochloride (20).
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].Br[C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([Br:16])[C:9]=2[N:10]=1.[OH-].[Na+].O1CCCC1>O>[Br:16][C:11]1[C:9]2[N:10]=[C:6]([S:4][CH2:1][CH:2]=[CH2:3])[S:7][C:8]=2[CH:14]=[C:13]([CH3:15])[CH:12]=1
Reactant: C=CCS
Reactant: Cc1cc(Br)c2nc(Br)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCSc1nc2c(Br)cc(C)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
1.0 g of allyl mercaptan prepared above, 3.1 g of 2,4-dibromo-6-methyl-benzothiazole, 0.4 g of sodium hydroxide, 10 ml of tetrahydrofuran and 10 ml of water were mixed together and the obtained mixture was stirred for 3 hours at room temperature and then extracted with ethyl acetate. The extract was dried with anhydrous sodium sulfate and evaporated to obtain the title compound in a liquid state (Yield: 92.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:25]=[CH:26][C:21]([CH2:19][CH3:20])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CCc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-ethylbenzene boronic acid according to the general procedure B. Obtained as an orange solid (689 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].[CH2:12](N(CC)CC)C.CI>O1CCCC1>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CI
Solvent: C1CCOC1
Product: CNCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (2-amino-ethyl)-carbamic acid-tert-butyl ester (5 g) and triethylamine (6.5 ml) in tetrahydrofuran (1000 ml) at 0° C. was added methyliodide (1.94 ml) dropwise over a period of 1 hour. The mixture was allowed to warm to ambient temperature and stirred for 72 hours before removal of solvents by evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO4) and solvent removed by evaporation to give the title compound (3.7 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:24]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:13][CH:14]([O:24][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:15][CH3:16]
Reactant: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reactant: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCC(C)OC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
Next, S(+)-2-octanol (50 g, 0.38 mol) was dissolved in dry pyridine (150 ml), and to the solution was dropwise added under cooling, a solution of 4'-benzyloxybiphenyl-4-carboxylic chloride (112 g, 0.35 mol) dissolved in dry toluene (150 ml), followed by agitating the mixture at about 50°-60° C. for 2 hours, thereafter adding water (300 ml) and toluene (300 ml), agitating the mixture, washing the separated toluene layer with 6N-HCl, then with 2N-NaOH aqueous solution and further with water until the washing water became neutral, drying the toluene layer with anhydrous sodium sulfate and distilling off toluene to obtain 4'-benzyloxybiphenyl-4-carboxylic acid 1-methylheptyl ester (53 g), dissolving this ester (53 g, 0.13 mol) in ethanol (500 ml) and reducing it in the presence of palladium/carbon (Pd/C) 5 g) to obtain 4'-hydroxy-4-(1-methyl-heptyloxycarbonyl)biphenyl (34 g). (ii) Preparation of 4-octyloxycarbonyloxybenzoic chloride
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[OH-:21].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:18](=[O:21])[NH2:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCOC(=O)c1ccc(NC2(C#N)CCCCC2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(NC2(C(N)=O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
550 mg (2.02 mmol) of 4-(1-cyanocyclohexylamino)-benzoic acid ethyl ester are dissolved in 20 ml of concentrated sulfuric acid. The reaction medium is stirred at room temperature for 5 hours. The reaction medium is poured gently onto ice, the pH is brought to 12 with sodium hydroxide, and the resulting mixture is extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The product is chromatographed on silica gel (60/40 heptane/ethyl acetate). The product 4-(1-carbamoyl-cyclohexylamino)benzoic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][C:20]#[C:21][CH2:22]Cl.O>CN(C=O)C>[Cl:18][CH2:19][C:20]#[C:21][CH2:22][N:2]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCC#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC#CCCl
Temperature: 80 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
To a solution of 1H-isoindole-1,3(2H)-dione (441 mg) in DMF (5 mL) were added potassium carbonate (829 mg) and 1,4-dichlorobut-2-yne (2.21 g) at room temperature. The reaction mixture was stirred at 80° C. for 5 hr. The reaction mixture was added to water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (202 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:15]=4)=[CH:5][C:4]=1[CH3:31])=O.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1COCC1>C(Cl)Cl>[CH3:31][C:4]1[CH:5]=[C:6]([C:9]2[CH:10]=[C:11]([C:28]([NH2:30])=[O:29])[C:12]3[NH:13][C:14]4[C:19]([C:20]=3[CH:21]=2)=[CH:18][CH:17]=[C:16]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH:15]=4)[CH:7]=[CH:8][C:3]=1[CH2:1][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3c2)ccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3c2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(4-formyl-3-methylphenyl)-7-morpholino-9H-carbazole-1-carboxamide (20 mg, 0.034 mmol), morpholine (0.05 mL, 0.574 mmol), sodium triacetoxyborohydride (100 mg, 0.472 mmol) were mixed with THF (5 mL) and CH2Cl2 (2 mL) in a sealed microwave vial. The mixture was stirred for 3 hr at r.t. The mixture was concentrated and purified using preparative HPLC to give titled product. MS (ESI) m/z 485.25 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.10 (s, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H, J=8.6), 7.67 (s, 1H), 7.62 (d, 1H, J=8.0), 7.47(s, 1H), 7.33 (d, 1H, J=7.6), 7.24 (s, 1H), 6.93 (dd, 1H, J=8.6, 1.9), 3.8 (t, 4H, J=4.7), 3.58 (bs, 4H), 3.49 (s, 2H). 3.19 (t, 4H, J=4.6), 2.45 (s, 3H), 2.4 (bs, 4H).