Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].CC(C)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O>[Cl:1][CH2:2][CH2:3][C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(CCCl)Nc1ccccc1

Procedure:
A mixture of 3-chloropropionyl chloride (300 ml) and acetone (600 ml) is added dropwise to a refluxing mixture of aniline (575 ml) and acetone (600 ml). The reaction mixture is refluxed for one hour, cooled in an ice bath, and poured into a mixture of 6N HCl (500 ml) and water (3.5 l). The resulting solid is filtered, washed with water, and dried, yielding the desired product, M.P. 114°-115.5° C.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[C:3]#[C:4][CH3:5].CC(C)([O-])C.[K+].Cl[C:14]1[N:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=1.Cl>CN(C=O)C.O>[CH3:1][CH:2]([O:6][C:14]1[N:15]=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=1)[C:3]#[C:4][CH3:5]
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CC#CC(C)O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)Oc1cnc(C(=O)O)cn1
Temperature: 75 °C
Yield: 65.3 %

Procedure:
50 ml RBF was charged with 3-pentyn-2-ol (2.063 ml, 22.08 mmol) in DMF (10 ml) and potassium t-butoxide (1.24 g, 11.04 mmol) was added portionwise while stirring (cooling in water bath). The mixture was stirred at room temperature for 10 min until all t-BuOK went into solution, then 5-chloropyrazine-2-carboxylic acid (500 mg, 3.15 mmol) was added in portions and the resulting brown suspension was heated at 75° C. for 45 min. The mixture was cooled to room temperature and diluted with water (˜20 ml) until all solids dissolved, then acidified with 2M HCl solution (˜5.5 ml) to pH 2. The resulting solution was extracted with EtOAc, organic layer was washed with water twice then with brine, filtered through pad of celite and concentrated in vacuo. The resulting suspension was diluted with 3 ml heptane/EtOAc (20:1) mixture then filtered. The solid was washed with heptane and dried in vacuo to afford 5-(pent-3-yn-2-yloxy)pyrazine-2-carboxylic acid (424 mg, 2.056 mmol, 65.2% yield) as tan solid. LC/MS (ESI+) m/z=207 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35]>N1C=CC=CC=1>[C:33]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18](=[O:19])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)(=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)C(=O)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Yield: 7.6 %

Procedure:
Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 9 mg, 0.021 mol) in pyridine (1 ml) was reacted with isobutyryl chloride (4.1 μl, 0.21 mmol) to yield the title compound (8 mg, 80%).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[CH2:22][CH:23]([CH3:25])[CH3:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:33][C:27]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=1[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:4]([N+:1]([O-:3])=[O:2])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:17][CH:16]=1)(=[O:20])=[O:19]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(Br)cc2)c(C)c1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: COC(=O)CCC(c1ccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1)[N+](=O)[O-]
Temperature: 120 °C

Procedure:
To a solution of methyl 4-nitrobutanoate (0.094 mL, 0.757 mmol), 4-bromo-N-(2,4-dimethylphenyl)-N-isobutylbenzenesulfonamide (200 mg, 0.505 mmol), di-tert-butyl(2′-methyl-[1,1′-biphenyl]-2-yl)phosphine (15.77 mg, 0.050 mmol) and cesium carbonate (197 mg, 0.606 mmol) in 1,2-dimethoxyethane (DME) (3 mL) at room temperature was added bis(dibenzylideneacetone)palladium(0) (14.51 mg, 0.025 mmol). The vial was flushed with nitrogen for 2 minutes then sealed and heated by microwaves (Emrys Optimiser) to 120° C. for 60 minutes. The reaction mixture was cooled then passed through a pre-packed silica (Si) cartridge, eluting with methanol (15 mL). The resulting filtrate was evaporated in vacuo then purified by mass directed autoprep (formic acid modifier). The relevant fractions were concentrated under a stream of nitrogen to give the required product (N70% pure), 96 mg, used directly in next step without further purification. LCMS [LCMS1] Rt 1.41 min, m/z (ES+) 463 (M+H).
Reaction SMILES: O[C:2]1[C:13]2[C:12]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[S:7][C:6]=2[N:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=1[S:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CC1CCc2sc3ncnc(O)c3c21
Product: CCOC(=O)CC1CCc2sc3ncnc(Cl)c3c21
Temperature: 110 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Two 2000-mL 4-necked round-bottom flasks were charged with a solution of 15.3 (200 g, 718.58 mmol, 1.00 equiv) in POCl3 (2000 mL) at room temperature. The resulting solution was stirred for 2 h at 110° C. in an oil bath. The reaction mixture was cooled to room temperature and concentrated under vacuum. The reaction was then quenched by the addition of 1000 mL of ice-water. The resulting solution was extracted with 3×500 mL of ethyl acetate and the organic layers were combined. The combined organic layers were washed with 2×500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 200 g (94%) of ethyl 2-[12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetate (15.4) as a light yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:14]2[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=3)[CH2:12][CH2:13]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3)CC2)CC1

Procedure:
From (4-chlorophenyl)(4-piperidyl)methanone hydrochloride (100 mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate C, 102 mg) by procedure A.1. Yield: 128 mg (74%). Light yellow solid. MS (m/z): 449.3 ([M+H]+).
Reaction SMILES: [O:1]1[C:12]2[C:4](=[CH:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]=[CH2:9])[O:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:21])C=1.ClC1C=C(C=CC=1)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:12]2[C:4](=[CH:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]2[O:21][CH2:9]2)[O:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc2c(c1)OCO2
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: c1cc2c(cc1CC1CO1)OCO2
Reaction time: 55 h
Yield: 39.3 %

Procedure:
16.2 g of safrole was dissolved in 100 ml of chloroform and to the mixture was added dropwise 20.7 g of m-chloroperbenzoic acid dissolved in 500 ml of chloroform at 0°-5° C. The resulting mixture was allowed to stand with slow stirring for 55 hours, while maintaining the temperature at 0° - 5° C. After the completion of the reaction, m-chlorobenzoic acid crystals were filtered and the filtrate was washed twice with 5% sodium hydroxide solution, and then with water. After drying over anhydrous sodium sulfate, the solvent was evaporated to obtain the residue. This was distilled under reduced pressure to give 7.0 g (yield 39.3%) of safrole oxide as colourless oily substance having a boiling point of 108° - 110° C/3 mmHg.
Reaction SMILES: [CH3:1][C:2](=O)[C@@H]1[C@]2(C)[C@H]([C@H]3C(=CC2)[C@]2(C)C(=CC(=O)C=C2)CC3)CC1.CS(O)(=O)=O.[CH3:29][C@@H:30]1[CH2:71][C@@H:70]2[C@:57]([CH3:74])([CH2:58][CH:59]=[C:60]3[C@H:69]2[CH2:68][CH2:67][C:66]2[C@:61]3([CH3:73])[CH:62]=[CH:63][C:64](=[O:72])[CH:65]=2)[C@H:31]1[C:32](=[O:56])[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=C(N3CCCC3)N=[C:42]([N:51]3[CH2:55][CH2:54]CC3)[N:41]=2)[CH2:36][CH2:35]1.CS(O)(=O)=O.CS(O)(=O)=O.C[C@@H]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1.Cl.C[C@@H]1C[C@@H]2[C@](C)(CC=C3[C@H]2CCC2[C@]3(C)C=CC(=O)C=2)[C@H]1C(=O)CN1CCN(C2C=C(N3CCCC3)N=C(N3CCCC3)N=2)CC1>>[CH2:55]([NH:51][C:42]1[N:41]=[C:40]([N:37]2[CH2:36][CH2:35][N:34]([CH2:33][C:32](=[O:56])[C@@H:31]3[C@:57]4([CH3:74])[C@H:70]([C@H:69]5[C:60](=[CH:59][CH2:58]4)[C@:61]4([CH3:73])[C:66](=[CH:65][C:64](=[O:72])[CH:63]=[CH:62]4)[CH2:67][CH2:68]5)[CH2:71][C@H:30]3[CH3:29])[CH2:39][CH2:38]2)[CH:45]=[CH:2][CH:1]=1)[CH3:54]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]12C
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(N3CCCC3)nc(N3CCCC3)n2)CC1
Agent: CS(=O)(=O)O
Agent: Cl
Product: CCNc1cccc(N2CCN(CC(=O)[C@H]3[C@H](C)C[C@H]4[C@@H]5CCC6=CC(=O)C=C[C@]6(C)C5=CC[C@@]43C)CC2)n1

Procedure:
The preferred amino substituted steroid (XI) is 16α-methyl-21-[4]2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione. More preferred is 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna1,4,9(11)-triene -3,20-dione monomethanesulfonate, 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna1,4,9(11)-triene-3,20-dione bismethanesulfonate and 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione hydrochloride. Most preferred is 16α-methyl-21-[4-[2,6-bis(1-pyrrolidinyl)4-pyrimidinyl]-1-piperazinyl]pregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C@@H:13]([O:15][C@@H:16]2[CH2:20][CH2:19][C@H:18]([NH2:21])[C@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:31][C:32]([NH2:34])=[O:33]>>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([C@@H:13]([O:15][C@@H:16]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:31][C:32]([NH2:34])=[O:33])[C@H:17]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H](O[C@@H]1CC[C@H](N)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC(=O)CI
Product: C[C@H](O[C@@H]1CC[C@H](NCC(N)=O)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared using the amine from Example 27 and iodoacetamide using essentially the same procedure as Example 10. Mass spec (NH3 /CI): 475 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:30][CH2:29][C:23]5([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:31])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[C:60](O)(=[O:62])[CH3:61]>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[C:6]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:30][CH2:29][C:23]5([CH2:28][CH2:27][N:26]([C:60](=[O:62])[CH3:61])[CH2:25][CH2:24]5)[CH2:22][CH2:21]4)[C:16]([CH3:31])=[CH:15][N:14]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: CC(=O)O
Reactant: Cc1cnc(Nc2ccc3c(C)n(C)nc3c2)nc1NC1CCC2(CCNCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC2(CCC(Nc3nc(Nc4ccc5c(C)n(C)nc5c4)ncc3C)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.7 %

Procedure:
To a solution of N2-(2,3-dimethyl-2H-indazol-6-yl)-5-methyl-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (201.5 mg, 0.4802 mmol), HOAT (106.4 mg, 0.7817 mmol) and EDCI (145.7 mg, 0.7600 mmol) in DCM/DMF (4 mL/1 mL) were added N,N-diethylethanamine (207.6 mg, 2.052 mmol) and acetic acid (36.7 mg, 0.611 mmol). The reaction was stirred at rt for 2 h. The reaction solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the crude product as a light yellow solid (92 mg). The crude product was recrystallized from acetone/MeOH (6 mL/0.5 mL) to give the title compound as a white solid (50.4 mg, 21.6%).
Reaction SMILES: [Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1.[I:12]N1C(=O)CCC1=O>CC#N>[Cl:1][C:2]1[O:11][C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][C:9]([I:12])=[C:4]2[CH:3]=1
Reactant: Nc1nccc2cc(Cl)oc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Nc1ncc(I)c2cc(Cl)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.5 %

Procedure:
A solution of 2-chlorofuro[2,3-c]pyridin-7-amine (9.0 g, 53.8 mmol) in MeCN (250 mL) was treated with N-iodosuccinimide (18.2 g, 80.8 mmol) added portionwise over a 5-10 min period. The mixture was stirred at RT for 16 h. The reaction was then quenched with 20% aqueous Na2S2O3 and stirred for 10 min. EtOAc (200 mL) was added and the phases separated. The organic phase was washed with 20% aqueous Na2S2O3 (50 mL), then water (2×100 mL) and finally with brine. After drying over Na2SO4, the organic extracts were filtered and concentrated in vacuo. The material was purified using flash chromatography (25% EtOAc:hexane) to afford 12.6 g (80%) of the title compound. 1H NMR (300 MHz CDCl3): δ 4.76 (br. s, 2H), 6.49 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([NH:23][NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1)=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]1[N:26]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]2=[N:24][N:23]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnc2ccc(F)cn12
Reaction time: 4 h
Yield: 77.2 %

Procedure:
Hexachloroethane (1.34 g, 5.65 mmol) was added portionwise to a solution of Intermediate 6a (917 mg, 2.83 mmol), triphenylphosphine (1.48 g, 5.65 mmol) and triethylamine (1.6 mL, 11.3 mmol) in dry THF (15 mL) at RT and stirred for 4 h. The resulting precipitate was filtered off and the filtrate evaporated. The residue was purified by SCX-2, eluting with MeOH followed by 2M NH3 in MeOH, to give the title compound as a buff-coloured foam (669 mg, 77%). LCMS (Method 4): Rt 2.48 min, m/z 307 [MH+].
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8]([OH:10])=O)[O:6][CH2:5][CH2:4][O:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[N:50]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[F:61])[C:49]([C:62]([O:64][CH2:65][CH3:66])=[O:63])=[CH:48]2>CN(C=O)C>[F:61][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=1[CH2:54][N:50]1[C:51]2[C:47](=[CH:46][C:45]([NH:44][C:8](=[O:10])[CH2:7][C:2]3([CH3:1])[O:3][CH2:4][CH2:5][O:6]3)=[CH:53][CH:52]=2)[CH:48]=[C:49]1[C:62]([O:64][CH2:65][CH3:66])=[O:63]
Reactant: CC1(CC(=O)O)OCCO1
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1Cc1ccccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(NC(=O)CC3(C)OCCO3)ccc2n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
140 mg (0.96 mmol) of (2-methyl-1,3-dioxolan-2-yl)acetic acid are added to 5 ml of DMF, and 547 mg (1.44 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and 186 mg (0.25 ml, 1.44 mmol) of N,N-diisopropylethylamine are added. 300 mg (0.96 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-indole-2-carboxylate from Example XXXVI are added. The mixture is stirred at RT for 3 hours. For work-up the DMF is removed using a rotary evaporator. The residue is taken up in dichloromethane and extracted with aqueous hydrochloric acid. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCO)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCOS(C)(=O)=O)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (178 mg, 0.57 mmol) in DCM (8 mL), Et3N (0.24 mL, 1.71 mmol) was added. After stirring for 5 min at 0° C., methanesulfonyl chloride (0.11 mL, 1.43 mmol) was added dropwise, and the resulting suspension was stirred at 0° C. for 1 h 15, then quenched with water and extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4) and concentrated in vacuo to obtain the title compound as an oil. LC-MS conditions A: tR=0.90 min, [M+H]+=391.03.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][C:12]=1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:33]#[N:34]>C1COCC1>[N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:11][C:12]=1[CH2:20][C:21]([NH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[C:33]#[N:34])=[O:23]
Reactant: N#Cc1ccncc1N
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccncc1NC(=O)Cc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LiHMDS (2.5 eq) was added to ethyl 2-benzimidazol-2-ylacetate (1.0 eq) in THF at −78° C. After 1 hour, 3-amino4-cyanopyridine (0.8 eq) in THF was added. The resulting mixture was allowed to warm to room temperature overnight. The mixture was quenched with NH4Cl (aqueous saturated solution) and extracted with EtOAc. The organic layer washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a brown solid. The crude material was purified by silica gel chromatography (5:1 EtOAc:hexane) to yield the desired product. LC/MS m/z 278.3 (MH+), Rt 1.88 minutes.
Reaction SMILES: [O:1]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C@@H:2]1[C:3]([O:5]C)=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23].C1(C)C(C)=CC=CC=1>CS(O)(=O)=O.CO>[OH:1][C@H:2]1[C:3](=[O:5])[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23][C@H:7]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: Nc1ccccc1S
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Solvent: CO
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
A mixture of 40 g of methyl (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate, 26.5 g of 2-aminothiophenol and 300 ml of xylene is heated at 110° to 120° C. for 1 hour, whereby the reaction mixture containing methyl (2S,3S)-3-[(2-aminophenyl)thiol]-2-hydroxy-3-(4-methoxylphenyl)propionate is obtained. 380 mg of methanesulfonic acid are added to the mixture and the mixture is refluxed for 7 hours. During the reaction, methanol formed is removed by the azeotropic distillation with xylene. The mixture is cooled to under 10° C. and then stirred for 1 hour. Precipitated crystals are collected by filtration, washed with cooled methanol and then dried, whereby 49.1 g of (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained. Yield: 84.8% m.p.: 204°-205° C. [α]D20 +115° (c=0.5, dimethylformamide)
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:27])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([N:20]4[CH2:25][CH2:24][CH:23]([NH:26][CH2:35][CH2:34][CH2:33][CH2:32][OH:31])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 120 mg (0.19 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride (preparation described above) and 57 μl (0.38 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30]>CN(C=O)C>[Cl:25][CH2:26][CH2:27][CH2:28][S:29]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:31])=[O:30]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: O=S(=O)(Cl)CCCCl
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 38a. Thus, 3-(4-piperidinyl)-5-(3-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 19) (25 mg, 0.076 mmol) was reacted with 3-chloropropane sulfonyl chloride (30 uL, 0.242 mmol) in DMF (4 mL) to give 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indazole-7-carboxamide, which was used in the next step without further purification.