Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodo-pyridine (10.0 g, 41.8 mmol) was dissolved in 200 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I) iodide (239 mg, 1.25 mmol) and trimethylsilylacetylen (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20). The desired product was obtained as a light brown semi solid (10 g, >100%). This material was used without any further purification for the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:13]([C@@:16]1([CH3:42])[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C@@H:19]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:18]([C@@H:36]([CH2:39][CH3:40])[CH:37]=[O:38])[C:17]1=[O:41])[CH:14]=[CH2:15]>C1COCC1.C(OCC)(=O)C>[CH2:13]([C@@:16]1([CH3:42])[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C@@H:19]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:18]([C@H:36]([CH:37]([OH:38])[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:39][CH3:40])[C:17]1=[O:41])[CH:14]=[CH2:15]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CCCO[Si](C)(C)C(C)(C)C)C1=O
Reaction time: 2 h

Procedure:
The Grignard reagent derived from of (3-bromopropoxy)(tert-butyl)dimethylsilane was prepared on 1.8 mmol scale according to Minguez, et al. Biorg. Med. Chem. 11, 3335, 2003 as a gray solution in THF (˜3 mL). About 1.5 mL of the Grignard regent was added slowly to a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (100 mg, 0.22 mmol; Example 91, Step C) in THF (1 mL) at ambient temperature. After 2 h, the reaction was diluted in ethyl acetate and washed with saturated ammonium chloride solution followed by sat. aq. NaCl solution. The organic layer was dried over sodium sulfate and concentrated. Purification by silica chromatography eluting with ethyl acetate/hexane provided the title compound as a mixture of diastereomers.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([C:12](=O)[NH2:13])[CH2:9]1)=O)(C)(C)C.[NH2:15][C:16]1[N:17]=[C:18]([NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[S:19][C:20]=1[C:21](=[O:30])[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29]>>[NH2:15][C:16]1[N:17]=[C:18]([NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([NH:13][CH2:12][CH:10]3[CH2:9][N:8]([CH3:6])[CH2:11]3)=[O:37])=[CH:34][CH:33]=2)[S:19][C:20]=1[C:21](=[O:30])[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29]
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)sc1C(=O)c1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CC(C(N)=O)C1
Product: CN1CC(CNC(=O)c2ccc(Nc3nc(N)c(C(=O)c4c(F)cccc4F)s3)cc2)C1

Procedure:
The title compound was prepared from 3-carbamoyl-azetidine-1-carboxylic acid tert-butyl ester after 1) reduction in a manner similar to similar to Step 2 in Example A39 and 2) subsequent coupling with 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) in a manner similar to Step 3 in Method A.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[OH-].[K+].[CH2:14]([O:16][C:17]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([CH3:33])[CH:27]=[C:26]2[O:34][CH2:35][CH2:36][CH2:37]Br)=[O:18])[CH3:15]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:37][CH2:36][CH2:35][O:34][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH2:21][CH2:20][CH2:19][C:17]([O:16][CH2:14][CH3:15])=[O:18])[CH:24]=3)[N:29]=[C:28]([CH3:33])[CH:27]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1O
Reactant: CCOC(=O)CCCOc1ccc2nc(C)cc(OCCCBr)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc2nc(C)cc(OCCCOc3c(N)nc(N)nc3CC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 2,4-diamino-6-ethyl-5-hydroxypyrimidine (0.308 g, 2.0 mmol), potassium hydroxide (0.123 g, 2.2 mmol) and 3-(6-(3-ethoxycarbonylpropoxy)-2-methylquinolin-4-yloxy)propyl bromide (0.821 g, 2.0 mmol) in DMF was stirred at 25° C. overnight. The DMF was evaporated to dryness and the residue was purified by column chromatography over silica gel (4% MeOH: 96% CH2Cl2 as eluent). The product was obtained as a light yellow solid (0.3578 g, 37%). 1H NMR (400 MHz, DMSO-d6): 0.90 (3H, t, J=7.5 Hz), 1.16 (3H, t, J=7.1 Hz), 2.08 (2H, m), 2.28 (4H, m), 2.48 (2H, t, J=7.0 Hz), 2.56 (3H, s), 3.86 (2H, t, J=5.8 Hz), 4.06 (4H, m), 4.41 (2H, t, J=5.8 Hz), 5.53 (2H, s), 6.11 (2H, s) 6.93 (1H, s), 7.31 (1H, dd, J=9.1, 2.6 Hz), 7.37 (1H, d, J=2.6 Hz), 7.76 (1H, d, J=9.1 Hz).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O1CCCC1>[CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]([CH3:32])([CH2:25][N:26]3[CH2:31][CH2:30][N:29]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:28][CH2:27]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4]
Reactant: CN(c1cccc2cc(C3=NCC(C)(CN4CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(C3=NCC(C)(CN4CCN(S(C)(=O)=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a mixture of N-methyl-N-{2-[5-methyl-5-(piperazine-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.28 g), triethylamine (0.17 ml) and tetrahydrofuran (6 ml) was added methanesulfonyl chloride (0.06 ml) at 0° C., and the reaction mixture was stirred overnight at room temperature, and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.26 g, yield 81%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [C:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[H-].[Na+].[Si:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][C:27]=1[CH2:34][CH2:35][CH3:36])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]2=[O:15])=[CH:28][C:27]=1[CH2:34][CH2:35][CH3:36])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20]
Reactant: CCOC(=O)n1c(=O)[nH]c2ccccc21
Reactant: CCCc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cn2c(=O)n(C(=O)OCC)c3ccccc32)ccc1O[Si](C)(C)C(C)(C)C
Yield: 64 %

Procedure:
To a solution of 0.295 g (1.43 mmol) of 1-carboethoxy-2-benzimidazolinone dissolved in 5.0 mL DMF was added 0.063 g (1.57 mmol) of a 60% oil dispersion of sodium hydride and the resulting mixture was stirred under a nitrogen atmosphere and gently warmed with a heat gun until the solids had dissolved and gas evolution had ceased. A solution of the product of step A in 2.0 mL DMF was then added and the reaction mixture was stirred for an additional 0.5 hours. The mixture was then quenched with 10% aqueous citric acid and extracted into ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and evaporated, and then the residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 0.088 g (64%) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32](O)=[O:33])[C:12]2=[O:35])=[CH:2]1.[CH2:36]([O:38][C:39]1[N:44]=[CH:43][C:42]([NH:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[CH3:37].P(Cl)(Cl)Cl>ClC(Cl)C>[CH2:36]([O:38][C:39]1[N:44]=[CH:43][C:42]([N:45]([CH:46]([CH3:47])[CH3:48])[C:32](=[O:33])[CH2:31][N:13]2[C:12](=[O:35])[CH:11]([CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]2=3)=[CH:41][CH:40]=1)[CH3:37]
Reactant: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Reactant: CCOc1ccc(NC(C)C)cn1
Solvent: ClP(Cl)Cl
Solvent: CC(Cl)Cl
Product: CCOc1ccc(N(C(=O)CN2C(=O)C(Cc3c[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 20.9 %

Procedure:
Following the procedure described for Example 2(A), [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid (Preparation 15) (300 mg, 0.65 mmol) was reacted with (6-ethoxy-pyridin-3-yl)-isopropyl-amine (Preparation 2(B)) (117 mg, 0.65 mmol) and PCl3 in dichloroethane at 100° C. Purification by medium pressure chromatography eluting with a solvent gradient (5% of 0.5% NH4OH/MeOH in CH2Cl2 to 10% of 0.5% NH4OH/MeOH in CH2Cl2) provided 85.1 mg of N-(6-ethoxy-pyridin-3-yl)-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CD3OD) δ 8.05 (d, 1H), 7.62 (m, 3H), 7.38-7.52 (m, 6H), 7.24 (d, 1H), 7.11 (m, 2H), 6.99 (t, 1H), 6.89 (m, 3H), 4.78 (m, 1H), 4.53 (m, 1H), 4.35 (q, 2H), 4.12 (m, 1H), 3.88 (t, 1H), 3.78 (dd, 1H), 3.69 (dd, 1H), 1.38 (t, 3H), 0.99 (m, 6H); MS 626.7 (M+1), 624.6 (M−1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH2:42][OH:43])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:25])([F:26])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH2:42][OH:43])[CH3:41]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(CO)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CC(CO)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-benzenesulfonamide (example B.9) according to general procedure II. Yellow solid. MS (ISP) 616.2 [(M−H−]; mp 248° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:13]=[C:12]([NH2:14])[NH:11][N:10]=2)[CH:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH:31]([C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1)=O.C(O)(=O)C.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:13]=[C:12]([NH:14][CH2:31][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[CH:35][CH:34]=3)[NH:11][N:10]=2)[CH:5]=[C:4]([C:15]([F:18])([F:16])[F:17])[C:3]=1[C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH:28]([CH3:30])[CH3:29])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2c(Cl)cc(Nc3n[nH]c(N)n3)cc2C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)S(=O)(=O)c1ccc(-c2c(Cl)cc(Nc3n[nH]c(NCc4ccc(C(=O)OC(C)(C)C)cc4)n3)cc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.2 %

Procedure:
To a solution of N3-(2-chloro-4′-(isopropylsulfonyl)-6-(trifluoromethyl)biphenyl-4-yl)-1H-1,2,4-triazole-3,5-diamine (135 mg, 294 μmol) in MeOH (3.5 ml) was added tert-butyl 4-formylbenzoate (85 mg, 412 μmol) followed by acetic acid (52.4 mg, 50 μl, 873 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (42.4 mg, 396 μmol) was added and the stirring was continued for 3 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and the resulting suspension was filtered to collect the solid. The crude material was purified by flash chromatography (silica gel, 24 g, 3% to 5% MeOH in DCM) to afford a white solid as desired product (94 mg, 49% yield). MS +m/z: 650 (M+H)+
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH3:18])[CH:11]=[O:12])[CH3:6]>ClCCCl>[CH2:17]([O:16][C:15]1[C:8]([O:7][CH2:5][CH3:6])=[CH:9][C:10]([CH:11]=[O:12])=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=1)[CH3:18]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: O=[N+]([O-])O
Solvent: ClCCCl
Product: CCOc1cc(C=O)c([N+](=O)[O-])cc1OCC
Temperature: 0 °C

Procedure:
2.13 ml of fuming nitric acid were added within 30 minutes to a solution, cooled to −30° C of 10 g of 3,4-diethoxybenzaldehyde in 185 ml of 1,2-dichloroethane. Subsequently, the reaction mixture was left to warm to 0° C. and was poured on to ice. The product was isolated by extraction. There were obtained 12.06 g of 4,5-diethoxy-2-nitro-benzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[N:10]([CH2:20][C:21]([N:23]([CH3:34])[C:24]3[CH:33]=[CH:32][C:27]4[N:28]=[C:29]([CH3:31])[O:30][C:26]=4[CH:25]=3)=[O:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:41](I)[CH3:42]>CN(C=O)C.O>[CH2:41]([O:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]([CH2:20][C:21]([N:23]([CH3:34])[C:24]3[CH:33]=[CH:32][C:27]4[N:28]=[C:29]([CH3:31])[O:30][C:26]=4[CH:25]=3)=[O:22])[C:11]2=[O:19])=[CH:16][CH:15]=1)[CH3:42]
Reactant: Cc1nc2ccc(N(C)C(=O)Cn3nc(-c4cccc(F)c4)c4ccc(O)cc4c3=O)cc2o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
2-(4-(3-fluorophenyl)-7-hydroxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (6.5 g, 14.19 mmol) was dissolved in DMF (60 mL), treated with K2CO3 (3.04 g, 21.2 mmol) and stirred at rt for 30 min. After cooling to 0° C., EtI (1.26 mL, 15.59 mmol) was added dropwise and the reaction was warmed to rt for 1 h. It was diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The organics were washed with brine (300 mL), dried over Na2SO4, and concentrated to give crude material which was purified by chromatography (40% EtOAc/hexane) to yield 2-(7-ethoxy-4-(3-fluorophenyl)-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (3.5 g) (487.52 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 1.39-1.42 (t, 3H), 2.62 (s, 3H), 3.24 (s, 3H), 4.22-4.24 (d, J=7.2, 2H), 4.72 (s, 2H), 7.37-7.49 (m, 5H), 7.58-7.65 (m, 3H), 7.71-7.73 (d, J=8.4, 1H), 7.90 (s, 1H).
Reaction SMILES: [C:1]([C@:11]([C:28]([OH:30])=[O:29])([OH:27])[C@:12]([C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)([OH:16])[C:13]([OH:15])=[O:14])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl.[Cl:32][C:33]1[CH:34]=[C:35]([C:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]>O.CO.CO>[C:17]([C@:12]([C:13]([OH:15])=[O:14])([OH:16])[C@:11]([C:1](=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([OH:27])[C:28]([OH:30])=[O:29])(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Cl:32][C:33]1[CH:34]=[C:35]([C@@:40]2([CH2:45][CH2:46][OH:47])[CH2:44][CH2:43][NH:42][CH2:41]2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine (R,R)-di-p-anisoyltartaric acid (0.8 g, 19 mmol) and aqueous 12 M hydrochloric acid solution (0.16 mL, 19 mmol) in water/methanol (10 mL)/(10 mL). Heat to reflux. Add dropwise, a solution of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 38.5 mmol) in methanol (10 mL). After 15 minutes, slowly cool to ambient temperature. Filter the solid that forms and rinse with water to give (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid: mp; 201-204° C. (dec). Analysis by HPLC, as described in Example 5.1.1 indicates an enantiomeric excess of 97%, (97% ee).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[CH:4]=1.[P:10]([O:17]CC)([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13]>>[CH2:8]([C:5]1[CH:4]=[C:3]([CH2:2][P:10]([O:14][CH2:15][CH3:16])(=[O:17])[O:11][CH2:12][CH3:13])[O:7][N:6]=1)[CH3:9]
Reactant: CCc1cc(CCl)on1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(CC)no1)OCC
Yield: 71.5 %

Procedure:
15 g of 5-chloromethyl-3-ethyl-isoxazole and 18 g of triethyl phosphite are slowly heated to 150° C. and kept at this temperature for 21/2 hours. After cooling, the residue is distilled under reduced pressure. 18.2 g of diethyl (3-ethylisoxazol-5-yl)-methanephosphonate, of boiling point 120°-121° C./0.2 mm Hg are obtained. Yield: 71.2%.
Reaction SMILES: Br[C:2](=[C:5]([NH:13][CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[C:3]#[N:4].[F:15][C:16]([F:21])([F:20])[C:17](=O)[CH3:18]>C(O)(=O)C.O>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5]2[N:13]([CH3:14])[C:17]([C:16]([F:21])([F:20])[F:15])=[CH:18][C:2]=2[C:3]#[N:4])=[CH:7][CH:8]=1
Reactant: CNC(=C(Br)C#N)c1ccc(Cl)cc1
Reactant: CC(=O)C(F)(F)F
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A solution of α-bromo-p-chloro-β-(methylamino)cinnamonitrile, (E)- or (Z)- (5.43 g, 0.02 mol) and trifluoroacetone (3.36 g, 2.7 mL, 0.03 mol) in acetic acid is heated at 80° C. for 1-2 hours, heated at 100° C. overnight, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain a gum. The gum is flash chromatographed using silica gel and a 15% ethyl acetate in heptane solution to give the title product as a yellow solid (1.7 g, mp 129°-131° C.) which is identified by 1H and 19FNMR spectral analyses.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:39][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:38])[F:36])[CH:29]=2)[N:24]=1
Reactant: Cc1nc(-c2cccc(OC(F)(F)F)c2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3cccc(OC(F)(F)F)c3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
28 mg (0.69 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.66 mmol) 3-chloromethyl-2-methyl-6-(3-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 234 mg (72%) of the title compound as slightly yellow powder.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:25])[CH2:11][CH2:12][CH2:13][N:14]2[C:19](=[O:20])[C@H:18]([CH3:21])[NH:17][CH2:16][C@H:15]2[C:22]([NH2:24])=[O:23])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:26][C:27]1[CH:32]=[C:31]([N:33]=[C:34]=[O:35])[CH:30]=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]>>[Cl:26][C:27]1[CH:32]=[C:31]([NH:33][C:34]([N:17]2[C@@H:18]([CH3:21])[C:19](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:4][CH2:5]4)[C@H:2]([OH:1])[CH2:9]3)=[O:25])[C@H:15]([C:22]([NH2:24])=[O:23])[CH2:16]2)=[O:35])[CH:30]=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37]
Reactant: C[C@@H]1NC[C@@H](C(N)=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)[C@H](C(N)=O)CN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 88 %

Procedure:
In analogy to the procedure described in the second part of example 120 step E, (2S,5S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-5-methyl-6-oxo-piperazine-2-carboxylic acid amide was reacted with 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) to give the titled compound in 88% yield as a colorless solid. MS: 574.3 (MH+, 1Cl).
Reaction SMILES: S(=O)(=O)(O)O.Cl[C:7]1[NH:8][CH2:9][CH2:10][N:11]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[OH-].[Na+]>CO.O>[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[N:15]=[C:7]1[NH:8][CH2:9][CH2:10][NH:11]1
Reactant: ClC1=NCCN1
Reactant: Nc1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccccc1N=C1NCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To 2-chloroimidazoline bisulfate (60.0 g, 300 mmoles) in methanol (600 ml) and water (150 ml) is added with stirring 2-chloroaniline (81.1 g, 67 ml, 636 mmoles). The heterogeneous mixture is stirred at ambient temperature overnight. After 20 hours the mixture is poured into ice water, made strongly alkaline with sodium hydroxide and extracted with dichloromethane twice. The organic extracts are washed once with water and once with saturated sodium chloride solution and then extracted with 2 N acetic acid (2×1 liter). The combined acid extracts are backwashed with dichloromethane, made strongly alkaline with sodium hydroxide, and once again extracted with dichloromethane twice. The dichloromethane extracts are combined, washed with water and then sodium chloride solution and finally dried and evaporated in vacuo. The solid residue (31 g) is dissolved in hot toluene, filtered, and diluted with hexane (total volume 3 liters). Colorless crystals separate which are filtered, washed with hexane and air-dried, to give 28.2 g of 2-(2-chlorophenylimino)imidazolidine, m.p. 133°-134° C.