Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.Cl.N1CCCCC1.O1CCOCC1.[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([CH2:29][CH2:30][CH:31]=[O:32])=[CH:23][C:22]=2[O:21]1>O>[OH:32][CH:31]1[O:6][C:2](=[O:5])[CH:3]=[C:30]1[CH2:29][C:24]1[CH:25]=[CH:26][C:27]2[O:28][CH2:20][O:21][C:22]=2[CH:23]=1
Reactant: O=CCCc1ccc2c(c1)OCO2
Reactant: O=CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: C1COCCO1
Product: O=C1C=C(Cc2ccc3c(c2)OCO3)C(O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.5 %

Procedure:
2.5 g (0.027 mol) of glyoxylic acid hydrate, 3.2 g (0.027 mol) of piperidine hydrochloride, and 30 mL of dioxane were mixed with stirring, whereupon water was added in dropwise fashion until a homogeneous solution resulted. 3-(3,4-Methylenedioxyphenyl)propionaldehyde (4.8 g, 0.027 mol) was then introduced and the solution allowed to stir at room temperature for 1 hour, then heated at reflux for 48 hours. At the end of this time the solution was concentrated, diluted with water, and extracted with EtOAc (2×100 mL). The organic layer was separated, dried (MgSO4) then concentrated to afford an oil. The crude oil was chromatographed over silica gel (150 g). Elution with 50% EtOAc-hexane afforded 1.8 g, 28% of the desired product as a light yellow oil.
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][C@@:14]2([C:26]([OH:28])=O)[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:11][CH:10]=1.[NH2:31][CH2:32][CH:33]([OH:40])[CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37].Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2([C:26]([NH:31][CH2:32][CH:33]([OH:40])[CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][CH3:37])=[O:28])[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:29][CH:30]=1
Reactant: CCC(C)(C)CC(O)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(Cc1ccc(Br)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C)(C)CC(O)CNC(=O)C1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (6.4 mL, 58.6 mmol) was added to an ambient temperature solution of 2-(4-bromobenzyl)-1-(tert-butoxycarbonyl)proline (5.0 g, 13 mmol), 1-amino-4,4-dimethylhexan-2-ol (1.89 g, 13 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.0 g, 15.6 mmol), and hydroxybenzotriazole (2.1 g, 15.6 mmol) in dichloromethane (51 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo to afford tert-butyl 2-(4-bromobenzyl)-2-{[(2-hydroxy-4,4-dimethylhexyl)amino]carbonyl}pyrrolidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI.O>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH:10]=2)[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1ncc(Cl)c(Nc2cccc(OC3CCCCO3)c2)n1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: CN(c1cccc(OC2CCCCO2)c1)c1nc(Cl)ncc1Cl
Temperature: 70 °C
Yield: 60 %

Procedure:
A solution of 2,5-dichloro-N-[3-(tetrahydro-2H-pyran-2-yloxy)phenyl]pyrimidin-4-amine (110 mg, 0.32 mmol) in acetonitrile (3 mL) was treated with potassium carbonate (89 mg, 0.65 mmol) followed by methyl iodide (60 μL, 0.97 mmol) and heated at 70° C. for 16 h. The reaction mixture was treated with additional methyl iodide (60 μL, 0.97 mmol) and heated at 70° C. for 11 h. The reaction mixture was cooled to 25° C., poured into water (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude oil. This material was purified by flash column chromatography to give the desired product (68 mg, 59%) as a clear oil. LCMS for C16H18Cl2N3O2 (M+H)+: m/z=354.0, 356.0.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.Cl.[C:37](=[NH:42])(OCC)[CH3:38].C(N(CC)CC)C>C(O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([C:37](=[NH:42])[CH3:38])[CH2:31][CH2:32]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:34][CH:35]=1
Reactant: CCOC(C)=N
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCNCC2)c2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(=N)N1CCC(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
15 mg (0.029 mmol) of 4-(4-chlorobenzoyl)-1-(4-piperidinyl-methyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate was dissolved in 5 ml of ethanol. 120 mg (1.7 mmol) of ethyl acetimidate hydrochloride and 0.50 ml (3.6 mmol) of triethylamine were added to the obtained solution, and they were stirred at 80° C. for 2 days. 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: Cl[CH2:2]/[CH:3]=[C:4]1/[C:5]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=2[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/1=2.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]2[N:29]=[CH:30][NH:31][C:27]=2[CH:26]=1>>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]2[N:29]([CH2:2]/[CH:3]=[C:4]3/[C:5]4[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=4[O:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/3=4)[CH:30]=[N:31][C:27]=2[CH:26]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]2[N:29]=[CH:30][N:31]([CH2:2]/[CH:3]=[C:4]3/[C:5]4[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][C:6]=4[O:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]/3=4)[C:27]=2[CH:26]=1
Reactant: COc1ccc2nc[nH]c2c1
Reactant: COC(=O)c1ccc2c(c1)/C(=C/CCl)c1ccccc1CO2
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1cnc3cc(OC)ccc31)c1ccccc1CO2
Product: COC(=O)c1ccc2c(c1)/C(=C/Cn1cnc3ccc(OC)cc31)c1ccccc1CO2

Procedure:
Compound h, 2.9 g, and 4.2 g of 5-methoxybenzimidazole were treated in a manner similar to Example 23 to give a 1:1 mixture of Compounds E-61a and E-62a. The mixture was separated and purified by silica gel column chromatography (eluting solvent, hexane:ethyl acetate:triethylamine=10:10:1) to give 0.8 g of methyl (E)-11-[2-(5-methoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound E-61a), 0.5 g of methyl (E)-11-[2-(6-methoxy-1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate (Compound E-62a) and 2.3g of the mixture of Compounds E-61a and E-62a.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[S:5][C:6]=1[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH3:31])=[O:29]>C(Cl)Cl>[C:11]([O:10][C:8]([NH:7][C:6]1[S:5][C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:2]=1[NH:1][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:9])([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1cc(N)c(NC(=O)OC(C)(C)C)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNc1cc(C(=O)OC)sc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution of methyl 4-amino-5-(tert-butoxycarbonylamino)thiophene-2-carboxylate 89 (0.037 mmol, 10 mg) in CH2Cl2 (1 mL), triethylamine (0.367 mmol, 51.2 μL) and methyl bromoacetate (0.184 mmol, 17.45 μL) were added and stirred at rt for 3 h. The reaction was quenched in water and extracted with CH2Cl2. The organic layer was dried with phaseseparator whereafter and concentrated under reduced pressure to give methyl 5-(tert-butoxycarbonylamino)-4-(2-methoxy-2-oxoethylamino)thiophene-2-carboxylate 90 (10 mg, 79%). NMR (400 MHz, CDCl3) 1.54 (s, 9H), 3.31 (br s, 1H), 3.77 (s, 3H), 3.79 (d, J=6.3 Hz, 2H), 3.82 (s, 3H), 7.38 (s, 1H), 7.54 (br s, 1H). (m/z)=345 (M+H)+.
Reaction SMILES: CCN=C=NCCCN(C)C.[OH2:12].ON1[C:18]2[CH:19]=[CH:20]C=C[C:17]=2[N:16]=N1.C[N:24]([CH:26]=[O:27])C>>[CH2:19]([CH2:18][C:17]([NH2:16])=[O:12])[CH2:20][C:26]([NH2:24])=[O:27]
Reactant: CN(C)C=O
Reactant: O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)CCCC(N)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
To the above amine was added N-[(N-BOC-(4-aminobutyl)-N-methylpyrrole-4-(N-methylpyrrole-2-carboxamido)-2-carboxamido)]glutaramide monocarboxylic acid (0.132 g, 0.256 mmol), EDCI (0.084 g, 0.439 mmol) and 1-hydroxybenzotriazole hydrate [HOBT] (0.030 g, 0.220 mmol) which was then dissolved in DMF (7.5 mL). Dissolution was aided by sonication and the suspension stirred under nitrogen at room temperature for three days with the flask covered with foil. At that time, the DMF was removed via kugelrohr apparatus (0.1 mm Hg, 60° C.). The residue was purified on a silica gel column using a CHCl3 to 7% MeOH/CHCl3 solvent system to give the desired product N-[(N-BOC-(4-aminobutyl)-N-methylpyrrole-4-(N-methylpyrrole-2-carboxamido)-2-carboxamido)]-N-[5-(3-benzyloxy-2-(2-chloroethyl)phenyl)benzofuran-2-carboxamido)]glutarodiamide as a tan solid (0.108 g, 52% yield). Rf=0.08 (5% MeOH/CHCl3). M.p. 80-84° C. 1H-NMR (500 MHz, DMSO-d6) 10.21 (s, 1H), 10.04 (s, 1H), 9.82 (s, 1H), 9.81 (s, 1H), 5.09 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H). FAB-MS (NBA) 949 (M+H+, 1). FAB-MS (NBA+K+) 987 (M+K+, 1). Accurate mass calculated for C50H57N8O9Cl+Na: calcd. 971.3835, obs. 971.3821.
Reaction SMILES: [CH2:1]([CH:6]1[CH2:12][CH:11]2[CH2:13][CH:8]([CH:9]=[CH:10]2)[C:7]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>[Pd].C(O)(C)C>[CH2:1]([CH:6]1[CH2:12][CH:11]2[CH2:13][CH:8]([CH2:9][CH2:10]2)[C:7]1=[O:14])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1CC2C=CC(C2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CCCCCC1CC2CCC(C2)C1=O
Temperature: 100 °C
Yield: 53.3 %

Procedure:
3-Pentylbicyclo[3.2.1]oct-6-en-2-one (130 g, synthesized as above) was placed in a stainless steel autoclave with isopropanol (30 g) and Pd/C (1.5 g). The mixture was placed under 300 psi of hydrogen gas, and heated at 100° C. until gas uptake ceased. The resulting material was then removed from the autoclave, filtered, and distilled to yield 3-pentylbicyclo[3.2.1]octan-2-one 70 g).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH:7]([N:10]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28][CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:24][CH:23]=3)[N:16]=2)=[CH:13][N:12]=[C:11]1[CH3:38])([CH3:9])[CH3:8].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH2:48]>CO.CC(C)=O>[CH:7]([N:10]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([S:28]([CH2:29][CH2:30][CH2:31][N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)(=[O:1])=[O:48])=[CH:26][CH:27]=3)[N:16]=2)=[CH:13][N:12]=[C:11]1[CH3:38])([CH3:8])[CH3:9]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(SCCCN4CCOCC4)cc3)n2)n1C(C)C
Reactant: O
Reactant: O=S([O-])OO
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: Cc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)CCCN4CCOCC4)cc3)n2)n1C(C)C
Reaction time: 4 h
Yield: 43 %

Procedure:
A solution of water (0.5 ml) and oxone (400 mg) was added to a solution of 4-(1-isopropyl-2-methylimidazol-5-yl)-2-[4-(3-morpholinopropylthio)anilino]pyrimidine (Method 85; 260 mg, 0.58 mmol) in MeOH (2.5 ml) and acetone (0.5 ml). The mixture was stirred for 4 hours, a solution of sodium metabisulphite (250 mg) in water (1 ml) was added and the mixture stirred for a further 20 minutes. The volatiles were removed by evaporation. Water (10 ml) was added to the residue and saturated aqueous sodium hydrogen carbonate solution added to basify the solution. The aqueous solution was extracted with EtOAc (2×25 ml), the extracts combined, washed with brine (10 ml), dried and evaporated. The residue was purified by chromatography on silica eluting with DCM/MeOH (98:2 increasing in polarity to 92:8). The purified product was dissolved in methanol (4 ml), 1M ethereal hydrogen chloride (270 μl) added and the volatiles removed by evaporation. The residue was triturated with ether to give the title compound (120 mg, 43%). NMR: 1.52 (d, 6H), 1.98 (br t, 2H), 2.62 (s, 3H), 2.88-3.00 (br m, 6H), 3.33 (t, 2H), 3.77 (br s, 4H), 5.53 (sept, 1H), 7.20 (d, 1H), 7.69 (s, 1H), 7.81 (d, 2H), 7.98 (d, 2H), 8.58 (d, 1H), 9.77 (s, 1H); m/z 485.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[CH2:6]([N:5]([CH2:8][CH3:9])[C:3](=[O:4])[CH2:2][N:10]([S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:7]
Reactant: Cc1ccc(N)cc1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)C(=O)CBr
Product: CCN(CC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)C)cc1

Procedure:
prepared by reaction of 2-bromo-N,N-diethylacetamide with p-toluidine and 4-isopropyl-benzenesulfonyl chloride
Reaction SMILES: [CH:1]([C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH:11]=[CH:10][C:9]1=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]2)=[C:2]=[CH2:3].[C:24]([O-:27])(=O)[CH3:25].[CH3:28][Cu]C.[Li].C[Li]>CCOCC.O>[C:24]([O:22][C@H:16]1[CH2:15][CH2:14][C@H:13]2[C@H:12]3[C@H:21]([CH2:20][CH2:19][C@:17]12[CH3:18])[C@:4]1([CH:1]=[C:2]=[CH2:3])[C:9](=[CH:8][C:7](=[O:23])[CH2:6][CH2:5]1)[CH2:10][C@H:11]3[CH3:28])(=[O:27])[CH3:25]
Reactant: C[Cu]C
Reactant: C=C=C[C@]12CCC(=O)C=C1C=C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)[O-]
Agent: [Li]
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: C=C=C[C@]12CCC(=O)C=C1C[C@@H](C)[C@H]1[C@@H]3CC[C@H](OC(C)=O)[C@@]3(C)CC[C@@H]12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Diene 10, prepared from alcohol 26 by the procedure of Example 4, is converted to its 17-acetate by the procedure of Example 11. The crude acetate (352 mg, 1 mMole) in ether (2 ml) is added to an ethereal solution of lithium dimethylcopper prepared from 300 mg (2 mMole) of cuprous iodide and 2 ml (4 mMole) of a 2 M solution of methyl lithium in ether (5 ml) at -30° C. After 1 hour, the solution is allowed to warm to 0° C., then poured into water and extracted with ether. The combined ethereal extracts are washed with brine, then dried and evaporated. Recrystallization from ethyl acetate/hexane yields the product 27.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][C:7]2([CH3:14])[CH3:13].C(N(CC)CC)C.[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl>C1C=CC=CC=1.CN(C)C1C=CN=CC=1.O>[CH3:14][C:7]1([CH3:13])[C:6]2[C:11](=[C:2]([O:1][CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[CH:3]=[C:4]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: CC1(C)CCC(=O)c2c(O)cc(C#C[Si](C)(C)C)cc21
Reactant: C[Si](C)(C)CCOCCl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CCC(=O)c2c(OCOCC[Si](C)(C)C)cc(C#C[Si](C)(C)C)cc21
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A solution of 8-hydroxy-4,4-dimethyl-6-trimethylsilanylethynyl-3,4-dihydro-2H-naphthalen-1-one (Intermediate 66, 1.67 g, 5.8 mmol) in anhydrous benzene was treated with triethyl amine (1.41 g, 11.6 mmol) and catalytic amount of 4-(dimethylamino)pyridine followed by 2-(trimethylsilyl)ethoxymethyl chloride (1.93 g, 11.6 mmol) and the resulting reaction mixture was refluxed for 3 days. It was cooled to ambient temperature, diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil that was subjected to flash column chromatography over silica gel (230-400 mesh) using 2-6% ethyl acetate in hexane as the eluent to afford the title product as a yellow oil (1.58 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)C=O.[H-].[Na+]>CCCCCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Clc1cc(Cl)nc(OCc2ccccc2)n1

Procedure:
4, 6-Dichloro-2-(methysulfonyl)pyrimidine (Compound III-5) (21.3 g, 93.8 mmol) and benzyl alcohol (Compound II-64) (10.1 g, 93.8×1.0 mmol) were introduced into a 500 ml eggplant type flask, to which dimethylformamide (150 ml) was added to form a solution. While stirring in ice bath, 60% sodium hydride (3.94 g, 93.8×1.05 mmol) which had been washed with hexane was added. After bubbling was ceased, ice bath was removed and the reaction solution was stirred for 2 hours at room temperature. The reaction mixture was poured onto ice and the separated organic matter was extracted with ethyl acetate. The organic phase was washed successively with diluted hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and thereafter, the solvent was distilled off. The residue was purified on silica gel column chromatography (Wakogel C300, ethyl acetate/hexane=1/50(v/v)) to obtain the compound (I-173) as an oily product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:36])(=[O:35])[N:15]([C@H:20]([CH2:33][OH:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH2:43]([O:45][P:46](Cl)([O:48][CH2:49][CH3:50])=[O:47])[CH3:44].[H-].[Na+]>C(OP(OCC)(OCC)=O)C>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14](=[O:36])(=[O:35])[N:15]([C@H:20]([CH2:33][O:34][P:46]([O:48][CH2:49][CH3:50])([O:45][CH2:43][CH3:44])=[O:47])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:12][CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CN([C@H](CO)CCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCOP(=O)(OCC)OC[C@H](CCCCNC(=O)OC(C)(C)C)N(CC(C)C)S(=O)(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.00 g (3.7 mmol) (1S)-{4-[(5-tert-butoxycarbonylamino-1-hydroxymethyl-pentyl)-isobutyl-sulfamoyl]-phenyl}-carbamic acid tert-butyl ester (VII) (example 1A, step D) is dissolved in 0.63 mL triethylphosphate and 10 mL THF at 0° C. under inert argon atmosphere. 0.63 mL (4.44 mmol) diethylchlorophosphate is added and then 0.25 g (6.2 mmol), NaH 60% in oil is added in portionwise. The mixture is allowed to warm to room temperature and left to stir for 2 h (LC-MS showed completion after 1 h). To the solution is added 20 mL of Amberlite XAD-2 resin and the slurry thoroughly mixed and added to 200 mL ice water. After stirring for 15 min. the resin suspension is filtered and the resin washed several times with distilled water (500 mL). The desired product is desorbed from the resin with acetone (5×50 mL), EtOAc (5×50 mL), the organic phase is then dried over Na2SO4. After evaporation of the solvent 2.66 g (89%) of clear oil is obtained. The crude product contains a fraction with two diethyl phosphates and is used as is in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:14][CH2:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][N:12]3[C:7](=[C:8]([C:22]([O:24][CH3:25])=[O:23])[CH:9]=[C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:11]3=[O:15])[C:6]=2[CH:26]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CC2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccc(Cl)cc3c12

Procedure:
32 g of methyl 10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate were heated under reflux for 16 hours in 350 ml of carbon tetrachloride with 16 g of N-bromosuccinimide in the presence of 280 mg of dibenzoyl peroxide. The mixture is left to cool and 24.3 ml of triethylamine were added thereto. The mixture was then again heated under reflux for 3 hours. After cooling, the mixture was treated with about 900 ml of methylene chloride, and the organic phase was washed once with 550 ml of 1N hydrochloric acid and thereafter dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel and was recrystallized from ethyl acetate. There was obtained methyl 10-chloro-4-oxo-3-phenyl-4H-benzo[a]quinolizine-1-carboxylate as yellow crystals of m.p. 169°-170°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[N:24]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([NH:32][C:33](=O)[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:27][CH:26]=3)=[O:22])=[CH:16][CH:15]=1.Cl>ClCCl>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][CH2:33][NH:32][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[F:47])[C:23]([C:21]([NH:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][CH:16]=1)=[O:22])=[CH:31]2
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)Nc1ccc(N)cc1)n2Cc1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CCNc1ccc2c(c1)cc(C(=O)Nc1ccc(NS(C)(=O)=O)cc1)n2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
22.5 mg (0.20 mmol) of methanesulphonyl chloride are dissolved in 1 ml of dichloromethane, and 38.9 mg (0.49 mmol) of pyridine are added. A solution of 100 mg (0.20 mmol) of N-(4-aminophenyl)-5-[(3,3-dimethylbutyl)amino]-1-(2-fluorobenzyl)-1H-indole-2-carboxamide hydrochloride (Example 57) in 1 ml of dichloromethane is added dropwise to this mixture, and the reaction mixture is stirred at RT overnight. For work-up, 22 ml of 1-molar hydrochloric acid are added, and the mixture is extracted repeatedly with dichloromethane. The combined organic phases are washed in each case once with saturated copper sulphate solution, saturated sodium bicarbonate solution and water. They are then dried over sodium sulphate and filtered, and the solvent is removed under reduced pressure. This gives 96.2 mg (73%) of the product.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]([CH3:12])[CH2:9][O:10][CH3:11])=[O:6].[H-].[Na+].CCOC(C)=O.O>C1COCC1>[CH3:11][O:10][CH2:9][C@@H:8]([N:7]1[CH2:2][CH2:3][NH:4][C:5]1=[O:6])[CH3:12]
Reactant: COC[C@H](C)NC(=O)NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC[C@H](C)N1CCNC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
A −20° C. solution of (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (1.092 g, 5.61 mmol) in THF (25 mL) was treated portion-wise with NaH (60% in mineral oil, 505 mg, 12.62 mmol), allowed to warm to RT and stirred overnight. The mixture was treated with EtOAc, water, then 5% citric acid, the layers separated and the organic layer washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford (S)-1-(1-methoxypropan-2-yl)imidazolidin-2-one (95 mg, 11%). MS (ESI) m/z: 159.1 (M+H+).