Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(COC(=O)[N:10]([C@@H:19]([C:21]2[N:30](COCC[Si](C)(C)C)[C:24]3=[N:25][CH:26]=[C:27](Br)[CH:28]=[C:23]3[N:22]=2)[CH3:20])COCC[Si](C)(C)C)C=CC=CC=1.[CH2:40]([C@@H:42]1[CH2:51][C:50]2[N:49]=[CH:48][N:47]=[C:46]([N:52]3[CH2:58][C:57]4[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][C:56]=4[O:55][CH2:54][CH2:53]3)[C:45]=2[CH2:44][CH2:43]1)[CH3:41]>>[CH2:40]([C@@H:42]1[CH2:51][C:50]2[N:49]=[CH:48][N:47]=[C:46]([N:52]3[CH2:58][C:57]4[CH:59]=[C:60]([C:27]5[CH:28]=[C:23]6[NH:22][C:21]([C@H:19]([NH2:10])[CH3:20])=[N:30][C:24]6=[N:25][CH:26]=5)[CH:61]=[CH:62][C:56]=4[O:55][CH2:54][CH2:53]3)[C:45]=2[CH2:44][CH2:43]1)[CH3:41]
Reactant: C[C@H](c1nc2cc(Br)cnc2n1COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)OCc1ccccc1
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc5nc([C@@H](C)N)[nH]c5c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using phenylmethyl{(1R)-1-[6-bromo-3-({[2-(trimethylsilyl)ethyl]oxy}methyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}({[2-(trimethylsilyl)ethyl]oxy}methyl)carbamate (reagent preparation 19) and {-4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.59 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.61 (s, 1H), 7.50 (d, 1H), 7.09 (d, 1H), 4.80 (m, 2H), 4.53 (m, 1H), 4.43 (m, 1H), 4.27 (m, 1H), 4.06 to 3.93 (m, 2H), 2.96 to 2.78 (m, 2H), 2.62 (m, 1H), 2.32 (m, 1H), 1.95 (m, 1H), 1.75 (m, 1H), 1.67 (d, 3H), 1.41 (m, 2H), 1.16 (m, 1H), 0.99 (t, 3H); MS (EI) for C27H31N7O: 470 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:15][C@@H:14]([C:16]([OH:18])=O)[C:13]1([CH3:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:42]([N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)[CH3:43]>C(Cl)Cl.CCN(CC)CC>[CH2:42]([N:44]1[CH2:49][CH2:48][N:47]([C:16]([C@@H:14]2[CH2:15][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]2([CH3:20])[CH3:19])=[O:18])[CH2:46][CH2:45]1)[CH3:43]
Reactant: CC1(C)[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reactant: CCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)[C@@H]2C[C@H](NC(=O)OCc3ccccc3)C2(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a stirred solution of (1R,3S)-3-(benzyloxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (1.0 g) in DCM (30 ml) at 0° C. EDCI (800 mg) and HOBt (700 mg) were added, after 10 minutes N-Ethylpiperazine (800 mg) and Et3N (3 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for 8 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water, saturated NaHCO3 solution, water, 1N HCl, water and saturated brine. The organic layer was concentrated under reduced pressure then the resulting crude was purified by silica gel column (100-200 mesh, elution 90% EtOAC in hexane) to afford the title compound as a syrup. Wt: 780 mg; Yield: 57.9%. 1H NMR and Mass complies with the required product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N+:11]=[N-:12])=[CH:6][C:5]=1[CH3:13].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]([F:27])([F:26])[F:25])=[CH2:23])[CH:19]=[C:18]([Cl:28])[CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:23][C:22]([C:20]3[CH:19]=[C:18]([Cl:28])[CH:17]=[C:16]([Cl:15])[CH:21]=3)([C:24]([F:25])([F:27])[F:26])[N:12]=[N:11]2)=[CH:6][C:5]=1[CH3:13]
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(N=[N+]=[N-])cc1C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)N=N2)cc1C
Temperature: 130 °C
Yield: 17.8 %

Procedure:
A mixture of 4-azido-2-methyl-benzoic acid methyl ester (made in analogy to methods described in, for example, Journal of Organic Chemistry, 2006, 71(15), 5822-5825) (820 mg, 3.4 mmol) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (preparation described in, for example, EP 1,731,512) (500 mg, 2.6 mmol) in toluene (20 ml) was heated at 130° C. for 48 hours. The reaction mixture was concentrated and the residue purified by column chromatography on silica gel (eluent: 3% v/v ethyl acetate in hexane) to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-[1,2,3]triazol-1-yl]-2-methyl-benzoic acid methyl ester as a gummy oil (200 mg).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([CH3:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(C)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@H]1CCC[C@@H]1c1ccnn1C
Yield: 109.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (0.20 g, 0.34 mmol) prepared in Example 43b, triethylsilane (0.10 mL), trifluoroacetic acid (0.50 mL) and dichloromethane (4.0 mL), to yield the title compound (0.16 g, 98%) as a colorless amorphous solid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][C:9]2[C:13]3[C:14]([N:16]=[C:17]([NH2:19])[NH:18][C:12]=3[NH:11][CH:10]=2)=[O:15])=[CH:5][CH:4]=[C:3]([C:20]([NH:22][C@H:23]([C:29]([O-:31])=[O:30])[CH2:24][CH2:25][C:26]([O-:28])=[O:27])=[O:21])[CH:2]=1.O.O.O.O.O.O.O.[Na+].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC(=O)[C@H](CCC(OCC)=O)NC(=O)C1C=CC(CCC2C3C(=O)NC(N)=NC=3NC=2)=CC=1)C>>[NH2:19][C:17]1[NH:18][C:12]2[NH:11][CH:10]=[C:9]([CH2:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:20]([NH:22][C@H:23]([C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:21])=[CH:2][CH:1]=3)[C:13]=2[C:14](=[O:15])[N:16]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Agent: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1

Procedure:
U.S. Pat. No. 7,138,521 discloses crystalline pemetrexed disodium heptahydrate. This heptahydrate form is prepared from N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]L-glutamic acid diethylester p-toluenesulfonic acid salt, which is saponified at a pH of between 2.5 to 3.5 to give N-[4-[2(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (“pemetrexed diacid”), of the following Formula II:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:7])[CH:8]=[C:9]([O:11][CH3:12])[N:10]=1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.50 g (2.7 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.37 g (2.7 mmol) 5-fluoroindoline and 0.42 mL (3 mmol) TEA were in 10 mL DMF placed. 0.97 g (3.0 mmol) TBTU were added and the reaction mixture was 2 h stirred at RT. The substance was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:19](OC=C)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([OH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]([O:18][C:19](=[O:21])[CH3:20])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: C=COC(C)=O
Agent: CCOC(=O)CC(O)c1ccc(OC)cc1OC
Product: CCOC(=O)CC(OC(C)=O)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1200 h

Procedure:
The mixture of 5.0 g (20 mmol) of ethyl 3-(2,4-dimethoxyphenyl)-3-hydroxypropionate, 10 ml of vinyl acetate and 2.0 g of lipase PS was stirred at room temperature for 50 days. After the lipase was removed by filtration, the filtrate was eluted by column chromatography (eluting solution; 9/1 of toluene/ethyl acetate) to obtain 3.5 g (35%ee) of (-)-ethyl 3-(2,4-dimethoxyphenyl)-3-hydroxypropionate and 1.5 g of (+)-ethyl 3-(2,4-dimethoxyphenyl)-3-acetoxypropionate, respectively.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCCCOc1cccc(CN2CCCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCCCOc1cccc(CN2CCCCC2)c1
Yield: 97.3 %

Procedure:
In a similar manner to that of Example 16 (ii) reaction of 4-[3-(piperidinomethyl)phenoxy]butyronitrile (2.58 g) and lithium aluminium hydride (0.46 g) gave 4-[3-(piperidinomethyl)phenoxy]butylamine (2.55 g) as an oil. This oil and 2-chlorobenzthiazole (1.81 g) were fused at 130° C. for 4 hours. The cooled residue was subjected to column chromatography on silica using dichloromethane:methanol:ammonium hydroxide (90:5:05) as eluant to give the title compound (1.6 g), m.p. 92°-93° C. (recrystallised from toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][N:12]1[C:20]([C:21]2[N:25]([CH3:26])[CH:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=2)=[C:19]2[C:14]([N:15]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:16](=[O:32])[N:17]([CH3:31])[C:18]2=[O:30])=[N:13]1.[CH2:37]([NH2:40])[CH2:38][NH2:39].C(P(=O)(OCC)OCC)#N>>[NH2:39][CH2:38][CH2:37][NH:40][C:27]([C:23]1[CH:22]=[C:21]([C:20]2[N:12]([CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)[N:13]=[C:14]3[C:19]=2[C:18](=[O:30])[N:17]([CH3:31])[C:16](=[O:32])[N:15]3[CH2:33][CH:34]([CH3:35])[CH3:36])[N:25]([CH3:26])[CH:24]=1)=[O:29]
Reactant: NCCN
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCN)cn3C)n(Cc3c[nH]c4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(5-chloro-1H-indol-3-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and ethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 551.15 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22](O)=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:22]([C:19]1([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[CH2:21][CH2:20]1)=[O:23]
Reactant: Nc1nc2ccccc2s1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3nc4ccccc4s3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
Benzothiazol-2-ylamine (30. mg, 0.20 mmol) and 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (38 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (DMF, 1 mL) containing triethylamine (84 μL, 0.60 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 80 mg, 0.21 mmol) was added and the solution was allowed to stir at room temperature for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography to yield the pure product (17 mg, 0.052 mmol, 26%). ESI-MS m/z calc. 324.1. found 325.0 (M+1)+. Retention time of 3.48 minutes.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[F:5][C:6]([F:20])([C:16]([F:19])([F:18])[F:17])[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.BrBr.N>C(O)(=O)C.O>[F:5][C:6]([F:20])([C:16]([F:17])([F:18])[F:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]=[C:2]([NH2:3])[S:1][C:14]=2[CH:15]=1
Reactant: Nc1ccc(OCC(F)(F)C(F)(F)F)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: N
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(OCC(F)(F)C(F)(F)F)cc2s1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
Potassium thiocyanate (4.27 g) is added to a solution of 4-(2,2,3,3,3-pentafluoropropoxy)aniline (2.65 g) in acetic acid (25 cc), and the mixture is stirred for 10 minutes at a temperature in the region of 20° C. To the solution thereby obtained, a solution of bromine (0.56 cc) in acetic acid (5 cc) is introduced dropwise in the course of 35 minutes at a temperature of between 22° C. and 35° C., and the mixture is then stirred for 16 hours at a temperature in the region of 20° C. The reaction mixture is poured into a mixture of water and ice (150 cc), alkalinized with 28% strength ammonia solution (35 cc) and extracted 3 times with ethyl acetate (170 cc in total). After settling has taken place, the organic solution is separated and washed with distilled water to pH 8, dried over magnesium sulphate, filtered and evaporated at 50° C. under reduced pressure (20 mm Hg; 2.7 kPa). The product obtained (3.2 g) is purified by chromatography on a column of silica (250 g; particle size: 0.063-0.200 mm) with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluant, and recrystallized in toluene (15 cc). 6-(2,2,3,3,3-Pentafluoropropoxy)-2-benzothiazolamine (1.27 g), m.p. 147° C., is obtained.
Reaction SMILES: [CH2:1]([CH:3]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:7]2[CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=[CH:20][C:6]=2[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]([CH3:24])[C:4](=[O:25])[CH:3]([CH2:1][CH3:2])[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[C:7]=2[CH:17]=1
Reactant: CCC1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1N=C(c2ccccc2Cl)c2cc(N)ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7.7 g (0.021 M) of rac-3-ethyl-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 85 ml of concentrated hydrochloric acid, treated with 18 g of stannous chloride and stirred at room temperature for 30 minutes. The mixture is poured into a mixture of ice and sodium carbonate solution, extracted with methylene chloride and the extract is dried over sodium sulphate, filtered and concentrated. After crystallisation from ethyl acetate/ether there is obtained rac-7-amino-3-ethyl-5-(o-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 198°-199° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:15][C:16](=[O:33])[CH2:17][CH:18]1[CH2:23][CH2:22][C:21]([N:30]([CH3:32])[CH3:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[Cl:35][Si](C)(C)C.CCOCC>CC(CC)=O>[ClH:35].[CH3:1][O:2][C:3](=[O:34])[C@@H:4]([NH:15][C:16](=[O:33])[CH2:17][CH:18]1[CH2:19][CH2:20][C:21]([N:30]([CH3:31])[CH3:32])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1
Reactant: C[Si](C)(C)Cl
Agent: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Solvent: CCOCC
Product: Cl
Reaction time: 0.17 h

Procedure:
(2S)-2-[2-(4-Dimethylamino-4-phenylcyclohexyl)acetylamino]-3-(1H-indol-3-yl)propanoic acid methyl ester (271 mg, 0.587 mmol) was dissolved in ethyl methyl ketone, and chlorotrimethylsilane (0.111 ml, 0.88 mmol) was added. After 1 h ether (30 ml) was added to the mixture and the mixture was stirred for a further 10 min. The hydrochloride was filtered off and obtained as a colourless solid in a yield of 96% (278 mg) with an m.p. of 239-241° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccccc1
Reactant: CSc1ccc(C=O)cc1
Product: CSc1ccc(C=CC(=O)c2ccccc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from commercial 4-(methylthio)benzaldehyde and acetophenone, 3-[4-(methylthio)phenyl]-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:36][CH:35]=2)[N:30](COCC[Si](C)(C)C)[N:29]=[C:28]3[NH:56][C:57](=[O:61])[CH2:58][CH2:59][CH3:60])[CH:20]=1.C(OCC)(=O)C>O1CCCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:35]=[CH:36][C:37]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:38][CH:39]=2)[NH:30][N:29]=[C:28]3[NH:56][C:57](=[O:61])[CH2:58][CH2:59][CH3:60])[CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3cccnc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3cccnc3)cc12
Yield: 84.2 %

Procedure:
7.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 700 mg of N-[5-(3-pyridyl)-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 2×75 cm3 of saturated sodium hydrogen carbonate solution and then with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 850 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is dried (90 Pa; 45° C.) to give 460 mg of N-[5-(3-pyridyl)-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of cream-coloured crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[CH2:12]=[O:13]>CO.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: Cc1c(Cl)cccc1[N+](=O)[O-]
Reactant: C=O
Solvent: CS(C)=O
Solvent: CO
Product: O=[N+]([O-])c1cccc(Cl)c1CCO
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Triton B (2 ml, 35% in MeOH) was added to a mixture composed of 2-chloro-6-nitrotoluene (25 g, 146 mmol) and paraformaldehyde (1.9 g, 60 mmol) in DMSO (20 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å) and was stirred at 90° C. After 2 h, the reaction mixture was neutralized with a few drops of conc. HCl, diluted with H2O (50 ml) and extracted with EtOAc (4×150 ml). The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by sublimation in a high vacuum (p=0.06 torr, oil bath temperature 95° C.). 2-(2-chloro-6-nitrophenyl)ethanol (8.01 g, 66%) was obtained in the form of bright yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[N:9][NH:10][C:6]=2[C:5]([O:11][CH3:12])=[CH:4][N:3]=1.ClC1C2C=NN([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)C=2C=CN=1>>[Cl:1][C:2]1[C:7]2[CH:8]=[N:9][N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[C:6]=2[C:5]([O:11][CH3:12])=[CH:4][N:3]=1
Reactant: Clc1nccc2c1cnn2C1CCCCO1
Reactant: COc1cnc(Cl)c2cn[nH]c12
Product: COc1cnc(Cl)c2cnn(C3CCCCO3)c12

Procedure:
C5 was converted to the product using the method described for synthesis of 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine P3 in Preparation P3. The product was obtained as a light yellow oil, which solidified upon standing. Yield: 120 mg, 0.448 mmol, 41%. LCMS m/z 268.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.11-8.12 (m, 1H), 7.72 (s, 1H), 6.12 (dd, J=10.0, 2.6 Hz, 1H), 4.06 (s, 3H), 4.04-4.10 (m, 1H), 3.69-3.77 (m, 1H), 2.51-2.62 (m, 1H), 2.12-2.21 (m, 1H), 2.00-2.08 (m, 1H), 1.5-1.8 (m, 3H).
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7](O)[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(O)cc1

Procedure:
The catalytic reduction was carried out in the same manner as in Example 1 except that the water-containing acetic acid was employed in an amount of 3 times (Example 15) or 8.8 times (Example 16) the weight of 4-hydroxymandelic acid. The yields of 4-hydroxyphenylacetic acid were 78% by mole (Example 15) and 95% by mole (Example 16).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:14])([CH3:13])[C:10]([NH2:12])=[O:11])#[CH:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([Cl:23])=[CH:18][N:17]=1.CCN(CC)CC>O1CCOCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:15][C:16]1[N:21]=[C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]([CH3:14])([CH3:13])[C:10]([NH2:12])=[O:11])[C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C#Cc1ccccc1C(C)(C)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A mixture of 2-(2-ethynylphenyl)-2-methylpropanamide A36 (0.060 g, 0.32 mmol), 2,4,5-trichloropyrimidine (48 μL, 0.42 mmol) and Et3N (0.18 mL, 1.3 mmol) in 1,4-dioxane (5 mL) was bubbled with N2 for 10 minutes. CuI (0.001 g, 0.006 mmol) and PdCl2(PPh3)2 (0.002 g, 0.003 mmol) were added and the reaction mixture was stirred at room temperature under a N2 atmosphere for 5.5 hours. The volatiles were removed in vacuo and the residue was purified by column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 10-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A37 as an off-white solid (0.067 g, 63%). LCMS-D: rt 3.33 min; m/z 334 [M+H]+.