Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.S(C)C.C[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2>ClCCCl>[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: BrB(Br)Br
Solvent: CSC
Solvent: ClCCCl
Product: O=C1Cc2cc(O)ccc2N1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
An oven-dried flask was charged with BBr3.SMe2 (2.80 g, 9.20 mmol) and 1,2-dichloroethane (15 mL). 5-Methoxyindolin-2-one (0.30 g, 1.84 mmol) was then added and the mixture was heated to reflux for 18 hours. The reaction was then cooled to room temperature and quenched with MeOH (1.0 mL). The mixture was then extracted into EtOAc washing with brine (3×). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo; the resulting residue was then purified by column chromatography (silica gel, 94:6 to 92:8, CH2Cl2/MeOH) to give 144 mg, 53% of a beige powder. MS ESI 149.9 [M+H]+, calcd for [C8H7NO2+H]+ 150.06
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[CH3:10][C:11]1([CH3:32])[CH:20]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[C:18]2[C:13](=[CH:14][C:15]([OH:31])=[CH:16][CH:17]=2)[O:12]1.CC1(C)CC(C2C=CC(C(F)(F)F)=CC=2)C2C(=CC(OCCN(C)C)=CC=2)O1>>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:31][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:20][C:11]([CH3:32])([CH3:10])[O:12]2)=[CH:17][CH:16]=1)[CH3:3]
Reactant: CCN(CC)CCCl
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Agent: CN(C)CCOc1ccc2c(c1)OC(C)(C)CC2c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: CCN(CC)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1
Yield: 49 %

Procedure:
Reaction of 2-diethylaminoethylchloride hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol by an analogous method to that described in Preparation 18 (c) gave the title compound as a colourless oil in 49% yield.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(Cl)Cl>C(OCC)(=O)C>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:8][CH2:9][C:10]#[CH:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CCCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 101.7 %

Procedure:
Triethylamine (12.2 mL) was added dropwise to a mixture of 3-butyn-1-ol (5.09 g) and 4-toluenesulfonyl chloride (16.95 g) in 50 nm of CH2Cl2 cooled by an ice bath. The mixture was allowed to warm to room temperature. After 21 hours, the mixture was poured into ethyl acetate (150 mL) and washed with 0.1M HCl (75 mL), saturated NaHCO3 (75 mL), and brine (75 mL) and the organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. Purification by flash chromatography (10% ethyl acetate/hexane) gave 16.57 g of the product as a colorless solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25](Br)=[C:26]([C:28]([O:30][CH2:31]C)=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC([I:72])=C(C([O-])=O)N=1)CC2)=O>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([I:72])=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)[O-])c(I)s1)CC2
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1I

Procedure:
Compound 47D was prepared in a similar manner to the synthesis of compound 34C by substituting compound 34B with compound 8C in step 3 of Example 34: APCI (+)/LC/MS: 707 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[C:19]2[CH2:18][N:17]([C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][C:15](=[O:29])[N:14]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[N:38]([CH3:42])[CH2:39][CH2:40][N:41]=4)=[CH:33][CH:32]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.[C:43](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[C:19]2[CH2:18][N:17]([C:20](=[O:28])[C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH2:16][C:15](=[O:29])[N:14]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[N:41]([CH3:43])[CH2:40][CH2:39][N+:38]=4[CH3:42])=[CH:33][CH:32]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CN1CCN=C1c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3c(Cl)cccc32)cc1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(F)(F)F
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CC[N+](C)=C1c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3c(Cl)cccc32)cc1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
12 mg (0.019 mmol) of 6-chloro-4-(4-chlorobenzoyl)-1-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)benzyl]-1,3,4,5-tetrahydrobenzo[e][1,4]-diazepin-2-on trifluoroacetate was dissolved in 5 ml of acetonitrile. 5 mg (0.036 mmol) of potassium carbonate and 0.010 ml of methyl iodide were added to the obtained solution, and they were stirred at room temperature for 4 hours. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[S:2]1(=[O:14])=[O:13].[H-].[Na+].Cl[CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.O>CN(C)C=O.C(OCC)(=O)C>[C:27]1([C:24]2[CH2:25][CH2:26][N:21]([CH2:20][CH2:19][CH2:18][N:1]3[C:11]4=[C:12]5[C:7](=[CH:8][CH:9]=[CH:10]4)[CH2:6][CH2:5][CH2:4][N:3]5[S:2]3(=[O:13])=[O:14])[CH2:22][CH:23]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCCCN1CC=C(c2ccccc2)CC1
Reactant: O=S1(=O)Nc2cccc3c2N1CCC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S1(=O)N(CCCN2CC=C(c3ccccc3)CC2)c2cccc3c2N1CCC3
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution of 5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (2.6 g) in dry N,N-dimethylformamide (10 cc) is added dropwise to a suspension of sodium hydride (0.45 g, 80% suspension in oil) in N,N-dimethylformamide (20 cc). After 15 minutes, stirring, a solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine (3.51 g) in N,N-dimethylformamide (10 cc) is added. The reaction mixture is heated to 80° C. for 90 minutes and is then cooled and poured into a mixture of water (100 cc) and ethyl acetate (200 cc). The organic phase is washed with water, is dried over magnesium sulphate and is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (0.2-0.063-mm particle size, 4-cm diameter, 50-cm height) with ethyl acetate as eluent and with 125-cc fractions being collected. Fractions 2 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization from ethyl acetate, 1-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (3.7 g) is obtained, melting at 120° C.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:16])(=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:7](=[NH:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:26])=[CH:20][CH:19]=1
Reactant: CCCCCCCC(=N)N
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCCCCC(=N)NC(=O)Nc1ccc(Cl)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.2 g. sodium in 200 ml. dry acetone, 17.8 g. octanamidine hydrochloride, and 15.3 g. 4-chlorophenyl isocyanate in 100 ml. benzene, there was obtained after recrystallization from acetonitrile 19.7 g. of the hydrochloride of 1-(4-chlorophenyl)-3-(octanimidoyl)urea; m.p. 156°-165°C.
Reaction SMILES: [C:1]([C:3]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Cl)=[O:5])#[N:2].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>CC(C)=O>[CH:14]1([NH:20][C:4](=[O:5])[C:3]([C:1]#[N:2])([CH3:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCC1
Reactant: CC(C#N)(C(=O)Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C#N)(C(=O)NC1CCCCC1)c1ccccc1
Temperature: 0 °C
Yield: 94.6 %

Procedure:
A solution of 9.75 g (0.05 mole) of 2-cyano-2-methyl-2-phenylacetyl chloride in 20 ml of acetone is cooled to 5° C., and a mixture of 5 g (0.05 mole) of cyclohexylamine, 5.2 g of triethyl amine and 10 ml of acetone is added to the solution under maintaining the temperature of the mixture below 10° C. The reaction mixture is poured into ice water, the separated solid is filtered off, and dried in vacuo. 12.12 g of N-cyclohexyl-2-cyano-2-methyl-2-phenylacetic acid amide are obtained; m.p.: 76°-78° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8])=[O:14]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
A solution of L-iso-Leucine (7.43 g, 56.6 mmol) in a mixture of dioxane (28 mL) and aqueous NaOH solution (93.5 mL, 2N) was treated with methyl chloroformate (8.75 mL, 113.3 mmol) dropwise, not allowing the internal temperature to rise above 50° C. The mixture was warmed to 60° C. and stirred for 18 hours, cooled to 25° C., and extracted with dichloromethane. The aqueous phase was cooled to 0° C., and its pH was adjusted to 1-2 with HCl (4 N). The mixture was partitioned between ethyl acetate and water, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product (10 g).
Reaction SMILES: [SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][SH:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:31])[C:22]([CH3:30])([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH3:23])=[CH:17][CH:16]=1>CC(N(C)C)=O.C(OCC)(=O)C>[SH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][S:7][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[O:31])[C:22]([CH3:23])([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH3:30])=[CH:19][CH:20]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Reactant: SCCSCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCSCCS)cc1)N1CCOCC1
Reaction time: 5 h

Procedure:
25.7 g (0.15 mol) of 2-mercaptoethylsulfide (purity 90%) are added to a suspension of 8.3 g (0.06 mol) of potassium carbonate in 50 ml of dimethylacetamide. A solution of 8.0 g (0.03 mol) 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one in 25 ml of dimethylacetamide is added dropwise at 85° C. over 60 min. After stirring for 5 h, the reaction mixture is cooled, diluted with ethyl acetate (100 ml), extracted with water (3×100 ml) to remove the carbonate and dimethylacetamide, dried over MgSO4, and concentrated under vacuum. The resulting yellow liquid (stench) is purified by flash chromatography on silica gel (hexane/ethyl acetate 85:15) to yield a pale yellow oil. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.750 (t, SH), 2.57 (t, 4H), 2.71-2.85 (m, 6H), 3.20 (t, 2H), 3.70 (t, 4), 7.31 (d, 2H), 8.51 (d, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH2:9]([NH2:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:17][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7]
Reactant: CCCCCCCCN
Reactant: O=C(Cl)CCCCBr
Product: CCCCCCCCNC(=O)CCCCBr
Yield: 92.1 %

Procedure:
5-Bromo-N-octylpentanamide (17.49 g) (mp μ30°) was prepared from 5-bromopentanoyl chloride (12.96 g) and octylamine (9.05 g) by an analogous method to that described in Example 2a.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[OH:15])[CH2:2][CH3:3].[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+].CN(C)[CH:24]=[O:25]>>[CH2:1]([C:4]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([CH2:12][CH2:13][CH3:14])[C:5]=1[O:15][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][C:16]([O:25][CH3:24])=[O:19])[CH2:2][CH3:3]
Reactant: CCCc1cc(CO)cc(CCC)c1O
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [Cs+]
Product: CCCc1cc(CO)cc(CCC)c1Oc1ccccc1CC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 1.014 g (4.87 mmol) of 2,6-di-propyl-4-hydroxymethylphenol dissolved in 10 mL of anhydrous dimethylformamide was added 2.379 g of cesium carbonate and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. A solution of methyl cx-bromo-phenylacetate dissolved in 2 mL DMF was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic layer was washed with brine, separated, dried (MgSO4), filtered and evaporated. The residual oil was purified on a silica gel flash chromatography column eluted with 20% EtOAc-hexane and combination of the purified fractions afforded 0.598 g (35%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.[N:27]1([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1.O>[Br:1][C:2]1[S:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:39]3[CH2:40][CH2:41][CH:36]([CH2:35][O:34][CH2:33][CH2:32][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:37][CH2:38]3)[C:4]=2[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ncnc2sc(Br)c(-c3ccccc3)c12
Reactant: C1CCN(CCOCC2CCNCC2)C1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1sc2ncnc(N3CCC(COCCN4CCCC4)CC3)c2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a stirred solution of 6-bromo-4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (0.820 g, 2.52 mmol) in THF (50 mL), was added diisopropylethylamine (0.65 mL, 3.78 mmol) and 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine (0.801 g, 3.78 mmol) in one portion, and the reaction left to stir at room temperature overnight. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The reaction was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography using DCM: MeOH (0-25%) as eluent to afford the named product (0.828 g, 66%).
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18](=[O:22])[CH:19](Br)[Br:20])=[CH:17][C:11]=3[O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[C:3]([C:23](=[O:27])[CH:24](Br)[Br:25])[CH:2]=1.CCN(CC)CC.P([O-])(OCC)OCC>C1COCC1>[CH:1]1[C:13]2[C:12]3[CH:14]=[CH:15][C:16]([C:18](=[O:22])[CH2:19][Br:20])=[CH:17][C:11]=3[O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]=2[CH:4]=[C:3]([C:23](=[O:27])[CH2:24][Br:25])[CH:2]=1
Reactant: O=C(c1ccc2c(c1)OCCCOc1cc(C(=O)C(Br)Br)ccc1-2)C(Br)Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc2c(c1)OCCCOc1cc(C(=O)CBr)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1′-(7,8-dihydro-6H-dibenzo[f,h][1,5]dioxonine-3,11-diyl)bis(2,2-dibromoethanone) (1b) (0.38 g, 0.61 mmol) in THF (7 mL) at 0° C. was added Et3N (0.09 mL, 0.61 mmol) and diethyl phosphite (0.24 mL, 1.82 mmol). The reaction mixture was gradually warmed to room temperature, stirred for 1 h and concentrated under reduced pressure. The residual contents were partitioned between EtOAc and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to yield an yellow oil (1c) which was used in the next step without further purification (0.15 g, 53%). m/z 468.9 (M+).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.O.[C:9]([O-:12])(O)=[O:10].[Na+].[O-]S([O-])=O.[Na+].[Na+].[C:20]1([CH3:26])[CH:25]=[CH:24]C=[CH:22][CH:21]=1>>[CH2:25]([C:20]1([CH2:21][CH3:22])[CH:26]([O:12][C:9](=[O:10])[CH:20]([CH2:21][CH3:22])[CH3:25])[NH:5][C:6]1=[O:7])[CH3:24]
Reactant: Cc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCC(C)C(=O)OC1NC(=O)C1(CC)CC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The material prepared above in Example 24, Method B, Step A (3.3 kg) was cooled to 5° C. under a N2 blanket and chlorosulfonyl isocyanate (2.1 L) was added with stirring over 1 hr. The mixture was then stirred at 8° C. for 45 hr and then cooled to 0° C., diluted with toluene (5 L), and then added to a mixture of H2O (60 L), ice (20 L), NaHCO3 (13 kg) and Na2SO3 (7.5 kg). This mixture was stirred at 20° C. for 13 hr before being filtered through Celite. The pad was washed with EtOAc (7 L) and the two layers of the filtrate were separated. The aqueous layer was further extracted with EtOAc (12 L) and the combined organic layers were washed with brine (8 L) before being concentrated in vacuo. Toluene (2 L) was then added to the residue and the solution was re-concentrated to dryness to give 4.57 kg of a light yellow oil which was of sufficient purity for use in the next step.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:43]1([CH3:55])[CH:48]=[CH:47][C:46]([S:49]([N:52]=[C:53]=[O:54])(=[O:51])=[O:50])=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:53]([NH:52][S:49]([C:46]5[CH:47]=[CH:48][C:43]([CH3:55])=[CH:44][CH:45]=5)(=[O:51])=[O:50])=[O:54])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NCCCCN)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nn3c(NCCCCNC(=O)NS(=O)(=O)c4ccc(C)cc4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Yield: 41.9 %

Procedure:
To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (28 mg, 0.05 mmol) in dichloromethane (5 mL) was added triethylamine (0.1 mL) and p-tolylsulfonyl isocyanate (0.012 mL, 0.08 mmol). The resultant solution was stirred at 0° C. for 1 hour and saturated aqueous sodium bicarbonate was added. The organic layer was washed with brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% methanol in dichloromethane) and recrystallization from dichloromethane-ether provided N-{[(4-{[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)amino]carbonyl}-4-methylbenzenesulfonamide (14 mg, 35%) as a yellow solid. 1H NMR (CDCl3): δ 8.03 (m, 1 H), 7.84–7.76 (m, 3 H), 7.58 (d, 2 H), 7.36–7.26 (m, 5 H), 7.01 (d, 2 H), 6.66 (m, 1 H), 6.34 (m 1 H), 6.04 (m, 2 H), 4.36 (m, 1 H), 3.91 (s, 3 H), 3.38–3.30 (m, 4 H), 2.36 (s, 3 H), 2.07 (m, 2 H), 1.82–1.54 (m, 10 H); MS m/z 669 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH3:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.Cl>CO.C(OCC)C>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:24][NH:25][CH3:26])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CN(Cc1ccccc1Sc1ccc2c(ccn2C(=O)OC(C)(C)C)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CNCc1ccccc1Sc1ccc2[nH]ccc2c1
Yield: 10.4 %

Procedure:
(2-Mercapto-benzyl)-methyl-carbamic acid tert-butyl ester (1.85 g, 7.30 mmol) in dry toluene (15 mL) is placed in an Emrys Optimizer EXP 20 mL tube. Tris(dibenzylideneacetone) dipalladium (334 mg, 0.37 mmol), bis(2-diphenylphosphinophenyl)ether (197 mg, 0.37 mmol), tert-butyl-5-bromoindole-1-carboxylate (2.38 g, 8.03 mmol) and potassium tert-butoxide (860 mg, 7.67 mmol) are added. The reaction vessel is sealed and subjected to microwave heating at 160° C. for 15 minutes. Upon cooling the mixture is poured onto a plug of silica and the product is eluted with ethyl acetate-heptane (1:4). 0.67 g (20%) of 5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylic acid tert-butyl ester is isolated and used in the next step without further purification. 5-{2-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylsulfanyl}-indole-1-carboxylic acid tert-butyl ester (0.67 g, 1.43 mmol) in methanol (15 mL) and diethyl ether saturated with hydrochloric acid (15 mL) is stirred at room temperature for 1 hour and concentrated in vacuo. Ice/water is added to the remanence and 28% aqueous NaOH is added until pH 9. The aqueous fraction is extracted with ethyl acetate (3×15 mL). Combined organic fractions are dried with MgSO4 and concentrated in vacuo. The product is purified by silica gel chromatography eluting with ethyl acetate-triethyl amine (100:4) followed by ethyl acetate-ethanol-triethyl amine (100:5:5). Upon evaporation of the volatiles, 40 mg (10%) of [2-(1H-indol-5-ylsulfanyl)-benzyl]-methyl-amine is isolated.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:28])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:26]#[N:27])[CH2:17][C:16](=[O:28])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(C2=Nc3ccc(I)cc3NC(=O)C2)c1
Yield: 98.8 %

Procedure:
Prepared from {2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-iodo-phenyl}-carbamic acid tert.-butyl ester (Example K1) (1.15 g, 2.3 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (880 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.[N-:19]=[N+:20]=[N-:21].[Na+].O>CN(C)C=O>[N:19]([CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1)=[N+:20]=[N-:21]
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc2c(c1)C(=O)c1ccccc1C2=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
10 g (0.039 mole) of 2-chloromethylanthraquinone [prepared according to G. Izoret, Ann. Chim., 7, 180 (1962)] are dissolved in 50 ml of N,N-dimethylformamide (DMF), and 2.53 g (0.039 mole) of sodium azide are added, with stirring. After 1 hour, the temperature is increased to 50° C. and the mixture is stirred at this temperature for 10 hours. 250 ml of water are added and the precipitate is filtered off. 9.5 g (92.3% of theory) of 2-azidomethyl-anthraquinone are obtained; melting point: 130° C. (decomposition).