Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C:6](=[O:8])[C:5]2[NH:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:30][C:27]1[CH:26]=[CH:25][C:24]([N:21]2[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][CH2:15][N:9]3[C:5]4[C:6](=[O:8])[CH2:7][N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]=4[CH:11]=[CH:10]3)[CH2:23][CH2:22]2)=[CH:29][CH:28]=1
Reactant: Fc1ccc(N2CCN(CCCCl)CC2)cc1
Reactant: CN1CC(=O)c2[nH]ccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN1CC(=O)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 79.7 %

Procedure:
A suspension of 200 mg (1 mmol) of Compound 12, 385 mg (1.5 mmol) of 1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine and 207 mg (1.5 mmol) of potassium carbonate in 15 ml of 2-butanone was refluxed for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: chloroform), whereby 335 mg of the title compound were obtained (yield: 80%).
Reaction SMILES: [H-].[Na+].[CH:3](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[N:16][OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][CH:19]([CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[CH2:20]Cl>>[CH:3](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[N:16][O:17][CH2:18][CH:19]([CH3:20])[CH2:22][N:23]1[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ON=C1CCCCC1=Cc1ccccc1
Reactant: CC(CCl)CN1CCN(C)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(CON=C1CCCCC1=Cc1ccccc1)CN1CCN(C)CC1

Procedure:
On starting from 2.4 g (0.1 moles) of sodium hydride, 20.1 g (0.1 moles) of 2-benzalcyclohexanone oxime and 20.76 g (0.11 moles) of 2-methyl-3-(4'-methylpiperazinyl)-propyl chloride, one proceeds in the way specified in Example 1.
Reaction SMILES: [CH3:1][CH:2]([N:11]([CH3:13])[CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.IC1C=CC=CC=1C(O)=O>CS(C)=O.C([O-])(O)=O.[Na+]>[CH3:12][N:11]([CH3:13])[CH:2]([CH3:1])[C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:10]
Reactant: CC(C(O)c1ccccc1)N(C)C
Agent: O=C(O)c1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C(=O)c1ccccc1)N(C)C
Yield: 93 %

Procedure:
N-Methylephedrine (500 mg, 2.79 mmol) was added to a solution of o-iodobenzoic acid I (7.8 g; 27.9 mmol) in DMSO (55 ml). After 48 hours the solution was diluted with NaHCO3 (2.5%, 30 ml) and extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with water (2×5 ml), dried over sodium sulfate and evaporated to dryness under vacuum. The residue was purified by distillation to give 460 mg (92%) of 2-dimethylamino-1-phenyl-propan-1-one (boiling at 113°-117° C./12 mm).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:24]3[C:25]([CH3:30])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=3[S:22][N:21]=2)[C:11]1=[O:31])[CH2:7][CH2:8][CH3:9])C.O.[Li+].[OH-]>O1CCOCC1>[CH3:30][C:25]1[C:24]2[C:20]([CH2:19][N:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:32])=[O:3])[C:11]3=[O:31])=[N:21][S:22][C:23]=2[CH:28]=[C:27]([CH3:29])[CH:26]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2ccccc21
Reaction time: 4 h

Procedure:
To a solution of product 3-[3-(4,6-Dimethyl-1,2-benzisothiazol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (23 mg, 0.051 mmol)) in 1,4-dioxane (5 mL) and water (1 mL) was added LiOH (2.4 mg, 0.1 mmol) at room temperature. The solution was stirred at the same temperature for 4 hours. The solution was concentrated and water was added to the residue. The solution was acidified by 12N HCl in an ice-bath. The solid that preciptate out from the solution was collected by filtration. The solid was dried under vacuum and was confirmed to be the desirable product (10 mg, 46%). LCMS (ESMS): m/z 424.18 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[C:7]=1[O:23][CH3:24].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[ClH:37]>CC(C)=O>[ClH:1].[ClH:37].[ClH:1].[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]4[NH:18][C:17]5[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=5[N:15]=4)[C:7]=3[O:23][CH3:24])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1c(SCCCCl)ccnc1CSc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CC(C)=O
Product: COc1c(SCCCN2CCN(c3ccccc3)CC2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 73 %

Procedure:
According to the procedure indicated in Examples 1), 3) and 6), reaction of 2-{[[4-(3-chloropropylthio)-3-methoxy-2-pyridinyl]methyl]thio}-1H-benzimidazole with N-phenylpiperazine and subsequent conversion into the hydrochloride in acetone gives the title compound; colorless crystals; m.p. 105° C., dec.; yield 73%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:25]([O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:32]2[CH:33]=[N:34][C:29]([O:28][CH:25]([CH3:27])[CH3:26])=[CH:30][CH:31]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][N:16]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)Oc1ccc(B(O)O)cn1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2n1-c1ccc(OC(C)C)nc1

Procedure:
The sub-title compound was prepared in accordance with Example 8(c) from 5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 8(b)) and 6-isopropoxypyridine-3-boronic acid (see step (b) above).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.ClC1C=CC(O[CH2:23][C:24]#[N:25])=CC=1.C(O)(=O)C.Cl>O1CCCC1>[Cl:7][C:8]1[N:9]=[C:10]([CH2:23][C:24]#[N:25])[C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CCc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 6.9 %

Procedure:
To a stirred solution of potassium t-butoxide (24.69 g, 220 mmol, 2.2 eq) in anhydrous tetrahydrofuran (150 ml) at -50° C. under nitrogen, a solution of 2-chloro-5-nitropyridine (15.85 g, 100 mmol) and (4-chlorophenoxy)acetonitrile (E. Grochowski et al., Bull. Acad. Pol. Sci. Ser. Sci. Chim., 11, 443 (1963)) (18.44 g, 110 mmol, 1.1 eq) in anhydrous tetrahydrofuran (150 ml) was added dropwise at such a rate that the reaction temperature was maintained at -40° to -50° C. with cooling in a dry ice/acetone bath. The resultant purple colored reaction mixture was then stirred at -78° C. under nitrogen for 1 hour, at which time glacial acetic acid (20 ml, 0.35 mol, 3.5 eq) was added to the reaction, and the mixture was allowed to warm to room temperature. A solution of 5% HCl (100 ml) was added to the reaction mixture and this aqueous mixture was extracted with ethyl ether (100 ml) and then with methylene chloride (2×100 ml). The extracts were combined, dried over magnesium sulfate, and passed through a silica gel filter (approximately 150 g) followed by methylene chloride (1200 ml). This filtrate was evaporated under reduced pressure, and the residual oil was chromatographed using silica gel (approximately 300 g) and eluted with 25% hexanes in methylene chloride to afford an oil (Rf =0.52 in methylene chloride) which was triturated in cold anhydrous ether to afford 6-chloro-3-nitro-2-pyridyl acetonitrile (1.37 g, 7%) as a white crystalline solid: mp, 121.5°-123.5° C. Further elution yielded another oil (Rf =0.48 in methylene chloride) which was triturated with cold anhydrous ethyl ether to afford (2-chloro-5-nitro-4-pyridyl)acetonitrile (1.87 g, 9%) as a white crystalline solid, m.p. 87°-89° C. IR (KBr) 3080, 2240, 1600, 1545, 1520, 1450, 1390, 1340, 1135 cm-1.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH2:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([CH2:22][CH2:23][CH3:24])[N:18]=1)(C)(C)C>C(Cl)Cl>[CH2:22]([C:19]1[N:18]=[C:17]([CH2:16][CH2:15][NH2:14])[O:21][N:20]=1)[CH2:23][CH3:24]
Reactant: CCCc1noc(CCNC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1noc(CCN)n1

Procedure:
TFA (6 ml) is added to a stirred solution of [2-(3-propyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (0.67 g, 2.62 mmol) in DCM (10 ml). After 1 hor the solvents are removed to afford the titled compound.
Reaction SMILES: [NH2:1][C@@:2]([C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[F:16])([CH3:8])[CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].ClCCl.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C([O-])(O)=O.[Na+].O.[Cl-].[Na+].O.C(OCC)(=O)C>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([F:16])=[C:9]([C@:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])([CH3:8])[CH2:3][C:4]([OH:6])([CH3:5])[CH3:7])[CH:14]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(O)C[C@](C)(N)c1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)C[C@](C)(NC(=O)CCl)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a vigorously stirred mixture of (S)-4-amino-4-(5-bromo-2-fluoro-phenyl)-2-methyl-pentan-2-ol (intermediate A14A) (2.22 g; 7.7 mmol) in sat. aqueous NaHCO3-sol. (25 ml) and dichloromethane (DCM) (35 ml) at 0° C. was added chloroacetyl chloride (672 μl, 8.5 mmol) and the mixture was stirred at 0° C. for 30 min Diluted with water, brine and ethyl acetate (EtOAc), separated phases, dried organic layer over sodium sulphate. Removal of the solvent in vacuum left the crude product as a colourless oil (3.11 g, 111%), which was used in the next step without further purification. MS (ISP): m/z=366.0 [(M+H)+], 368.0 [(M+2+H)+] and 370.0 [(M+4+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([F:15])[CH:9]=2)[N:5]=[C:4]([C:16]([O:18]C)=[O:17])[C:3]=1[Cl:20].[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[C:10]([F:15])[CH:9]=2)[N:5]=[C:4]([C:16]([OH:18])=[O:17])[C:3]=1[Cl:20]
Reactant: COC(=O)c1nc(-c2ccc(I)c(F)c2)cc(N)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cc(-c2ccc(I)c(F)c2)nc(C(=O)O)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.4 %

Procedure:
To a 100-mL round bottom flask, equipped with a stir bar was added methyl 4-amino-3-chloro-6-(3-fluoro-4-iodophenyl)picolinate (0.284 g, 0.699 mmol), 1.0 N sodium hydroxide (2.79 mL, 2.79 mmol) and methanol (5.0 mL). The reaction was allowed to stir for 18 hours at room temperature. The solvent was then removed with a rotary evaporator. The resulting solid was diluted with H2O, which was adjusted to pH-3.0 with 1 N HCl, and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (0.056 g, 21%).
Reaction SMILES: NC(=O)CC1C2C(=CC=CC=2OCCCP(=O)(O)O)N(CC2C=CC=C(Cl)C=2)C=1CC.C[O:33][P:34]([CH2:38][CH2:39][CH2:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[N:47]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=1)[C:46]([CH2:59][CH3:60])=[C:45]2[CH2:61][C:62]([NH2:64])=[O:63])(=[O:37])[O:35]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[NH2:64][C:62](=[O:63])[CH2:61][C:45]1[C:44]2[C:48](=[CH:49][CH:50]=[C:42]([O:41][CH2:40][CH2:39][CH2:38][P:34](=[O:33])([OH:37])[OH:35])[CH:43]=2)[N:47]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([Cl:58])[CH:53]=2)[C:46]=1[CH2:59][CH3:60]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1cccc(Cl)c1
Agent: CCc1c(CC(N)=O)c2c(OCCCP(=O)(O)O)cccc2n1Cc1cccc(Cl)c1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CO
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(O)O)ccc2n1Cc1cccc(Cl)c1
Reaction time: 0.75 h
Yield: 64.5 %

Procedure:
[3-[[3-(2-Amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]propyl]phosphonic acid. [[3-[[3-(2-Amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (99 mg, 0.2 mmol) and 0.21 mL (1.6 mmol) of trimethylsilyl bromide in 2 mL of methylene chloride was stirred for 16 hours, 5 mL of MeOH added, stirred 0.75 hours and concentrated at reduced pressure. The residue was crystallized from EtOAc/MeCN/HOAc/water to give 60 mg (65% yield) of [3-[[3-(2-amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-5-yl]oxy]propyl]phosphonic acid, mp, 203°-205° C.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][C:24]=1[OH:33])=[O:22])[CH3:19]>>[OH:33][C:24]1[CH:25]=[C:26]([CH2:29][C:30]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH2:15][CH3:16])=[O:31])[CH:27]=[CH:28][C:23]=1[C:21]([O:20][CH2:18][CH3:19])=[O:22]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1O
Reactant: CCCC(N)c1ccccc1N1CCCCC1
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from 1-(2-piperidino-phenyl)-1-butylamine and 4-ethoxycarbonyl-3-hydroxy-phenylacetic acid.
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH2:10]([N:12]([CH2:24][CH3:25])[C:13](=[O:23])[C:14]1[CH:22]=[CH:21][C:19]([OH:20])=[C:16]([O:17][CH3:18])[CH:15]=1)[CH3:11]>>[CH3:3][CH:2]([O:20][C:19]1[CH:21]=[CH:22][C:14]([C:13]([N:12]([CH2:24][CH3:25])[CH2:10][CH3:11])=[O:23])=[CH:15][C:16]=1[O:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CCCC(C)Br
Reactant: CCN(CC)C(=O)c1ccc(O)c(OC)c1
Product: CCN(CC)C(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1

Procedure:
2-bromo-6-methyl-heptane was reacted with vanillic acid N,N-diethyl amide to obtain p-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-N,N-diethyl-benzamide (boiling point = 180°-182°C/0.1 mmHg);
Reaction SMILES: [CH2:1]([C@:4]1([CH2:30][CH2:31][CH2:32][CH2:33][B:34]2[O:38][C:37]([CH3:40])([CH3:39])[C:36]([CH3:42])([CH3:41])[O:35]2)[C:9](=[O:10])[O:8][C@@H:7](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)[N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:2]=[CH2:3].C(=O)=O.N.[Li]>CC#N.C1COCC1>[CH2:1]([C@:4]([NH:5][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:30][CH2:31][CH2:32][CH2:33][B:34]1[O:35][C:36]([CH3:41])([CH3:42])[C:37]([CH3:39])([CH3:40])[O:38]1)[C:9]([O:8][CH3:7])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: N
Agent: O=C=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC#N
Product: C=CC[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 57.7 %

Procedure:
A three-necked RBF equipped with nitrogen inlet tube and dry ice condenser was charged with (3R,5R,6S)-tert-butyl 3-allyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate (4.60 g, 8.00 mmol) and THF (10 mL). After cooling the condenser to −78° C. and the flask to −45° C. (CO2 (s), CH3CN), ammonia (80 mL) was condensed into the flask. Once complete, lithium metal (0.55 g, 80 mmol, small pieces) was carefully added over 10 min. After stirring an additional 40 min, the reaction mixture was carefully quenched with NH4Cl (s) until the solution became clear. The bath was removed and the ammonia was allowed to evaporate over night. The resulting residue was diluted with ethyl acetate and washed successively with 0.5N HCl and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was dissolved in 50% methanol in toluene (80 mL, 0.1 M) and treated with TMSCHN2 (2.0 M in hexanes) until the pale yellow color persisted. With TLC indicating the reaction complete, the excess TMSCHN2 was quenched with acetic acid until the solution became clear. The solution was concentrated, diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (R)-methyl 2-allyl-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as colorless oil (1.9 g, 58%). Rf 0.46 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 5.70-5.52 (m, 1H), 5.49-5.36 (m, 1H), 5.05 (dd, J1=13.8 Hz, J2=1.2 Hz, 1H), 3.73 (s, 3H), 3.09-2.96 (m, 1H), 2.50 (dd, J1=13.8 Hz, J2=7.8 Hz, 1H), 2.29-2.10 (m, 1H), 1.78-1.65 (m, 1H), 1.43 (s, 9H), 1.42-1.26 (m, 4H), 1.23 (s, 12H), 0.74 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C21H38BNO6: expected 411.3. found 412.3 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][OH:73])[CH2:67][CH2:66]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH2:71][CH2:72][OH:73])[CH2:67][CH2:66]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NN1CCN(CCO)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NN2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (48 mg, 0.11 mmol, 1 eq), DIPEA (36 μL, 0.22 mmol, 2 eq) and TBTU (39 mg, 0.12 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 15 min before the addition of 2-(4-aminopiperazin-1-yl)ethanol (19 mg, 0.13 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before concentrating in vacuo and purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-(4-(2-hydroxyethyl)piperazin-1-yl)-3-methoxybenzamide (24 mg, 39%).
Reaction SMILES: [C:1]([O:4][N:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)[NH2:7])(=O)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:1]([CH3:2])[O:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)ON=C(N)c1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(I)cc2)no1
Reaction time: 24 h

Procedure:
To a solution of the product obtained in Step B above (9.7 g, 31.9 mmol) in 300 ml of toluene there are added 150 mg of para-toluenesulphonic acid and the reaction mixture is heated at reflux, using a Dean-Stark installation, for 24 hours. The mixture is evaporated to dryness and dried using a vacuum pump.
Reaction SMILES: Cl.[SH:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[CH2:13]([CH:15]([CH2:19][CH2:20][CH2:21][CH3:22])[C:16](Cl)=[O:17])[CH3:14].[Cl-].[NH4+]>ClCCl>[SH:2][CH2:3][CH2:4][NH:5][C:16](=[O:17])[CH:15]([CH2:13][CH3:14])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NCCS
Reactant: CCCCC(CC)C(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(CC)C(=O)NCCS
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
22.7 g of 2-mercaptoethylamine hydrochloride (0.2 mol) and 32.4 g of triethylamine (0.32 mol) were introduced in suspension in 130 ml of dichloromethane at 0° C.-5° C. Over the course of 25 minutes, 16.8 g of 2-ethylhexanoyl chloride (0.1 mol) were added dropwise. The batch was stirred at 0° C. to 5° C. for 1 hour, at 40° C. for 1.5 hours, and then at room temperature for 12 hours. 70 ml of saturated ammonium chloride solution were added and a phase separation was carried out. This was repeated twice and the organic phases were combined, dried over sodium sulfate, and freed of their solvent under reduced pressure. The residue obtained was purified by column chromatography (97 toluene:3 methanol).
Reaction SMILES: [NH2:1][NH2:2].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8](Cl)(=[O:10])=[O:9]>>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8]([NH:1][NH2:2])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: NN
Product: NNS(=O)(=O)c1cccs1

Procedure:
In the reaction, excess hydrazine in the presence of a solvent, advantageously a lower alkanol, is reacted with the 2-thiophenesulfonyl chloride to form a 2-thiophenesulfonyl hydrazine. In the reaction, the 2-thiophenesulfonyl chloride is gradually added to the hydrazine solution which is maintained at a low temperature, advantageously between about 5° and up to about 15° C. The reaction mixture is then allowed to warm to room temperature, the solvent is removed in vacuo and a mixture of a heavy oil and a fluffy solid results. This mixture is treated with water and the solid is dissolved and the oil separated therefrom. This mixture of oil and water, which contains the hydrazine hydrochloride from the first reaction, is then placed in a flask containing a bromine solvent, advantageously chloroform, crushed ice is added thereto and to the resulting slurry bromine is added at such a rate that the reaction temperature remains below about 10° C. After the bromine has been added and the bromine color has dissipated, the layers are separated, the chloroform layer is dried over an appropriate desiccant, advantageously anhydrous magnesium sulfate, and the chloroform removed in vacuo to leave a yellow oil which crystallizes on addition of hexane to give the 2-thiophenesulfonyl bromide.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 5.0 g (19.3 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 4.32 g (23.2 mmol) piperazine 1-carboxylic acid tert-butyl ester using 9.86 mL (57.9 mmoL) DIPEA in 50 mL dioxane. The reaction mixture is stirred at 80° C. over night. The solvent is removed under reduced pressure. The residue is taken up in water extracted three times with ethylacetate. The combined organic layers are dried over MgSO4 filtered off and the solvent is removed under reduced pressure. The residue is purified via NP-chromatography (DCM/MeOH 75/25 as eluent) yielding 7.2 g (92%) of the desired product, which is used without further purification for the next step.